Scholarly article on topic 'Endocytic regulation of cytokine receptor signaling'

Endocytic regulation of cytokine receptor signaling Academic research paper on "Biological sciences"

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Cytokine & Growth Factor Reviews
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{Internalization / Endocytosis / Trafficking / Endosome / "Multivesicular body" / Clathrin / Dynamin / "Cytokine receptor" / TNF / Interleukin / Interferon / Lymphotoxin / Signaling / NF-κB / Jak / STAT}

Abstract of research paper on Biological sciences, author of scientific article — Jaroslaw Cendrowski, Agnieszka Mamińska, Marta Miaczynska

Abstract Signaling of plasma membrane receptors can be regulated by endocytosis at different levels, including receptor internalization, endocytic sorting towards degradation or recycling, and using endosomes as mobile signaling platforms. Increasing number of reports underscore the importance of endocytic mechanisms for signaling of cytokine receptors. In this short review we present both consistent and conflicting data regarding endocytosis and its role in signaling of receptors from the tumor necrosis factor receptor superfamily (TNFRSF) and those for interleukins (ILRs) and interferons (IFNRs). These receptors can be internalized through various endocytic routes and most of them are able to activate downstream pathways from endosomal compartments. Moreover, some of the cytokine receptors clearly require endocytosis for proper signal transduction. Still, the data describing internalization mechanisms and fate of cytokine receptors are often fragmentary and barely address the relation between their endocytosis and signaling. In the light of growing knowledge regarding different mechanisms of endocytosis, extending it to the regulation of cytokine receptor signaling may improve our understanding of the complex and pleiotropic functions of these molecules.

Academic research paper on topic "Endocytic regulation of cytokine receptor signaling"


Cytokine-èâQagi^yth Factor

Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx


Mini review

Endocytic regulation of cytokine receptor signaling

Jaroslaw Cendrowski1, Agnieszka Maminska1, Marta Miaczynska*

International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland


Signaling of plasma membrane receptors can be regulated by endocytosis at different levels, including receptor internalization, endocytic sorting towards degradation or recycling, and using endosomes as mobile signaling platforms. Increasing number of reports underscore the importance of endocytic mechanisms for signaling of cytokine receptors. In this short review we present both consistent and conflicting data regarding endocytosis and its role in signaling of receptors from the tumor necrosis factor receptor superfamily (TNFRSF) and those for interleukins (ILRs) and interferons (IFNRs). These receptors can be internalized through various endocytic routes and most of them are able to activate downstream pathways from endosomal compartments. Moreover, some of the cytokine receptors clearly require endocytosis for proper signal transduction. Still, the data describing internalization mechanisms and fate of cytokine receptors are often fragmentary and barely address the relation between their endocytosis and signaling. In the light of growing knowledge regarding different mechanisms of endocytosis, extending it to the regulation of cytokine receptor signaling may improve our understanding of the complex and pleiotropic functions of these molecules.

© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND

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Article history: Received 8 June 2016 Accepted 13 July 2016 Available online xxx






Multivesicular body



Cytokine receptor





1. Introduction

Endocytosis is coupled to regulation of signaling initiated by plasma membrane receptors. Initially, internalization of the activated receptors was considered only as a means for signal attenuation, but now it is clear that endocytosis also regulates the duration of receptor signaling as well as specificity of signaling outputs (reviewed in Barbieri et al. [1]). Endosomes can serve as mobile signaling platforms facilitating formation of multiprotein signaling assemblies and therefore enabling efficient signal transduction in space and time. Signaling events that are initiated at the plasma membrane may continue at the endosomal compartments and terminate by incorporation of the receptor

into the intraluminal vesicles (ILVs) of the multivesicular bodies (MVBs).

Although a great number of biochemical and imaging approaches have been undertaken to study how different endocytic routes affect receptor signaling, they have been applied to only a few model receptors with a major focus on epidermal growth factor receptor (EGFR) [2]. Consequently, the review articles published so far have described the involvement of endocytosis in regulation of receptor tyrosine kinases (RTKs), such as EGFR, or G protein-coupled receptors (GPCRs), such as neurotransmitter or chemokine receptors [3-5]. Conversely, no reviews comprehensively summarize the role of endocytosis in signaling of cytokine receptors.

Abbreviations: CIE, clathrin-independent endocytosis; CME, clathrin-mediated endocytosis; DRM, detergent-resistant microdomains; EGFR, epidermal growth factor receptor; GPI-AP, glycosylphosphatidylinositol-anchored proteins; IFN, interferon; IFNAR, type I interferon receptor; IFNGR, type II interferon receptor; IFNR, interferon receptor; IL, interleukin; ILR, interleukin receptor; ILV, intraluminal vesicle; JNK, c-Jun N-terminal kinase; LT|3R, lymphotoxin b receptor; MVB, multivesicular body; M|3CD, methyl-|3-cyclodextrin; PI3K, phosphoinositide 3-kinase; RTK, receptor tyrosine kinase; TNF, tumor necrosis factor; TNFRSF, tumor necrosis factor receptor superfamily. * Corresponding author at: International Institute of Molecular and Cell Biology, Ksiecia Trojdena 4, 02-109 Warsaw, Poland.

E-mail address: (M. Miaczynska). 1 These authors contributed equally to this work.

1359-6101/© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (


J. Cendrowski et al./Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx

In the present review we focus on tumor necrosis factor receptor superfamily (TNFRSF), interleukin receptors (ILRs) and interferon receptors (IFNRs). As opposed to RTKs (tyrosine kinases) and TGFb receptor superfamily (serine/threonine kinases) they do not possess any intrinsic kinase activity and unlike GPCRs they do not transmit signals through G proteins. Instead, they depend on multiple signaling adaptors that mediate inflammatory and stress responses via signaling pathways involving NF-kB and MAPK (TNF receptor and IL-1 receptor superfamilies) or STAT and MAPK (receptors for IFNs and most of the ILs).

1.1. Mechanisms of receptor internalization

Receptor-mediated endocytosis is initiated at the plasma membrane by several distinct internalization mechanisms (Fig. 1). Their traditional division is based on the involvement of clathrin protein (clathrin-mediated endocytosis, CME) or its absence (clathrin-independent endocytosis, CIE). In CME, activated receptor induces recruitment of clathrin adaptors, such as the AP2 complex, while the subsequent formation of the clathrin coat stabilizes the membrane curvature and drives the invagination. In the final step, the vesicle is released from the plasma membrane by the large GTPase dynamin that assembles around the bud neck [6-8].

The mechanisms ofclathrin-independent internalization routes are less well defined. In fact, CIE is a common designation for several distinct internalization pathways, which depend on actin polymerization and its regulators, such as actin polymerizing factors and Rho GTPases [9]. Clathrin-independent internalization often takes place at the plasma membrane microdomains called

lipid rafts, that initially were viewed as the sole common feature of many CIE routes. Lipid rafts are enriched in cholesterol and glycosphingolipids, that create a liquid-ordered microenvironment in a less ordered surrounding. Lipid rafts are important domains for assembly of complexes transducing extracellular signals. Several examples are presented in this review, whereas other well established signaling events initiated in lipid rafts are T-cell receptor-dependent signaling cascades [10] or H-Ras-mediated Raf activation [11]. Due to their small size, native lipid rafts cannot be observed in standard light microscopy, that was a reason for using rather crude techniques to study their function. One of them is cholesterol depletion, which can potentially affect non-raft elements of the plasma membrane. Another approach enables separation of cell membranes to detergent-soluble or detergent-resistant fractions, the latter containing lipid raft microdomains. However, beside other limitations, this technique cannot distinguish the plasma membrane from intracellular membranes. Therefore, the data acquired with both methods have to be interpreted with caution and need validation with more precise approaches [11].

Detailed molecular mechanisms and functional classification of the CIE pathways are under intense research and their nomenclature is a matter of debate. Still, they can be subdivided depending on the involvement of dynamin. The best studied dynamin-dependent CIE is caveolar internalization [12]. Caveolins are integral membrane proteins resident in the lipid rafts. In the nonmuscle cells, caveolins 1 and 2 bind additional adaptors and coat small membrane domains, forming a cup-shaped invagination called caveolae. Another well-defined CIE route is IL-2 receptor (IL-2R) endocytosis, described in detail later in this review. Briefly,

Fig. 1. Receptor-mediated internalization and endocytic trafficking routes. Plasma membrane receptors can be internalized by means of clathrin-mediated (CME) or clathrin-independent (CIE) endocytosis. CIE often occurs at the plasma membrane microdomains called lipid rafts and can be subdivided based on involvement of dynamin in scission of internalized vesicles and on involvement of the listed molecular regulators. After internalization, receptors are trafficked to early endosomes from where they are sorted to recycling endosomes or multivesicular bodies (MVB). Recycling endosomes return the receptors to the plasma membrane, while MVBs sequester them through incorporation into intraluminal vesicles (ILV). Subsequent maturation of MVBs to late endosomes and their fusion with lysosomes leads to degradation of ILVs and their cargo. Increasing acidification of endosomal lumen is marked by progressive color change from blue to grey (see main text for details).


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IL-2R requires activities of dynamin and actin-modulating GTPases Rac1 and RhoA for internalization [13]. Recently, IL-2R was described as a cargo of fast endophilin-mediated endocytosis (FEME), where endophilins cooperate with dynamin and actin cytoskeleton in scission of vesicles formed in a clathrin-indepen-dent manner [14,15].

Other CIE pathways do not require dynamin activity but instead involve different mechanisms of vesicle scission from the plasma membrane which remain unresolved. They are mainly characterized by the internalized cargo and several crucial components. Flotilins can induce membrane invaginations and mediate endocytosis of fluid-phase components and GPI-anchored proteins (GPI-AP). Another route is described by internalization of GPI-APs, first trafficking to plasma membrane-derived clathrin-indepen-dent carriers (CLICs) and then to the specialized GPI-AP enriched early endosomal compartment (GEEC) [16,17]. This CLIC/GEEC route is driven extracellularly by galectin 3, that clusters receptors and induces the membrane curvature [18], and intracellularly by activation of Rho GTPase Cdc42 that induces actin polymerization [19]. Various cargo can internalize through this entry portal, including GPI-APs, transmembrane proteins and considerable amounts of extracellular fluids. Similar cargoes can enter the cell by endocytosis regulated by ADP ribosylation factor 6 (Arf6), a plasma membrane localized small GTPase [9]. Moreover, large volumes of extracellular fluid but also some receptors, can be internalized by macropinocytosis [20].

1.2. Endocytic sorting

Internalized cargo, independently of the entry mechanism, can be either recycled back to the plasma membrane or sorted towards degradation. The two routes diverge at the stage of early endosomes, also called sorting endosomes, marked by small GTPase Rab5 and its effectors EEA1 or APPL1 [21-23]. Subsequent sorting events are mediated by different subsets of endosomal compartments.

The recycling of receptors is necessary to renew their pool at the plasma membrane for another cycle of ligand import. It can proceed from the early endosomes directly to the plasma membrane, regulated by Rab4 [24], or through Rab11-positive recycling endosomes [25,26]. In fact, in the absence of a degradative mark (such as ubiquitin), recycling is the default route for receptors.

Alternatively, if the receptor undergoes ubiquitylation on the plasma membrane, it will be sorted from early endosomes towards degradation. Ubiquitylated cargo is recognized at the limiting membrane of the early endosomes by hepatocyte growth factor regulated tyrosine kinase substrate (Hrs), the component of the Endosomal Sorting Complex Required for Transport-0 (ESCRT-0) [27,28]. The four ESCRT complexes from 0 to III sequentially assemble on early endosomes, clustering receptors and driving formation of the intraluminal vesicles (ILVs), to which the receptors are targeted [29] (Fig. 1). Formation of ILVs is prerequisite for maturation of multivesicular endosomes (MVEs), named also multivesicular bodies (MVBs), which are considered transition structures between early and late endosomes [30]. Other hallmarks of such maturation are the increasing acidification to pH ~5.5 and exchange of Rab proteins from Rab5 to Rab7, called the Rab conversion [31].

The Rab7-positive late endosomes fuse with the lysosomes. Enzymes present in the lysosomes degrade their contents [32], including the receptor-enriched ILVs. The lysosomes are the last compartments in the degradative route and the most acidified, reaching pH 4.6 [33], but like other endosomes they are dynamic organelles undergoing reformation after fusion events [34].

1.3. Mechanisms of endocytic regulation of receptor signaling outputs

If we follow routes of receptor endocytosis, it turns out that every step of the trafficking can affect the signaling output. Firstly, internalization can attenuate signaling by restricting amounts of the receptor available for an extracellular ligand. For example, upon WNT binding the Frizzled receptor is internalized and degraded, that is necessary for proper embryonic development [35].

Secondly, for some receptors membrane surfaces of endosomes serve as platforms for assembly of signaling complexes and therefore more discretely modulate signal transduction. This is the case for G-protein-coupled receptors (GPCRs) that remain associated with b-arrestins, both at the plasma membrane and endo-somes, enabling signal transduction from the two locations [36-39]. In addition, endosomes may serve as platforms for unique signals, not initiated elsewhere. As endosomes are rich in phosphatidylinositol 3-phosphate, they can recruit proteins that have a FYVE domain, which binds this lipid [40]. It was shown that TGFb signaling utilizes adaptors containing a FYVE domain, such as SARA (Smad anchor for receptor activation) [41] and endofin [42] to activate transcription factors Smad 2/3 and Smad4, respectively. Endosomes in dendritic cells were also shown to serve as specialized platforms for sensing of pathogens by the cytosolic NOD2 receptor [43].

Thirdly, the fate of receptors is regulated by the endocytic sorting with two possible and contrasting outcomes. The signal will be either attenuated, when receptor is sorted to ILVs and can no longer associate with the cytoplasmic adaptors, or enhanced, if the receptor is recycled to the plasma membrane to restore the pool available for the ligand. This mechanism can be also coupled to specific internalization routes. The best studied example is the trafficking of EGFR. This receptor was shown to undergo CME when exposed to low doses of the ligand and to follow a CIE if high ligand concentrations were applied. It was proposed that EGFR internalized via CME is recycled to the cell surface that prolongs the signaling. In contrast, clathrin-independent internalization preferentially committed the receptor to degradation [44].

The effects of internalization and trafficking of cytokine receptors presented in this review mostly lack this level of understanding, but many hints suggest that endocytosis and sorting play a major role in regulating cell response to cytokines.

2. TNFR superfamily receptors

The tumor necrosis factor receptor superfamily (TNFRSF) consists of 29 receptors, all being type I transmembrane proteins. They are activated by ligand-induced multimerization and operate through interactions of a receptor cytoplasmic tail with signaling adaptors. Nine of them, such as TNFRI, Fas (CD95) and TRAIL receptors, possess a cytoplasmic interaction module called the death domain (DD) which mediates proapoptotic signaling. TNFR1 is a pleiotropic receptor as it can induce both canonical NF-kB as well as proapoptotic pathways [45]. The canonical NF-kB signaling is mediated by association of the receptor with RIP1 kinase and TRADD and TRAF2 adaptors (complex I), followed by subsequent IkBa degradation and activation of NF-kB dimer RelA:p50. The key events of the proapoptotic cascade initiation include association of TRADD and RIP1 with FADD and caspase-8 forming cytoplasmic complex II [46]. The role of endocytosis in the function of death receptors has been reviewed [47,48].

Other receptors from this superfamily are non-death receptors, such as LTbRand CD40, that induce pro-survival MAPK and NF-kB pathways. The latter involves canonical NF-kB signaling, but also the noncanonical NF-kB branch driven by accumulation of NIK


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kinase, processing of the inhibitory p100 to the active p52 and formation of RelB:p52 transcription factor.

2.1. TNFR1

TNFR1 is activated by TNFa, which is the founding member of the TNF ligand superfamily. Upon activation, the death domain of TNFRI associates with adaptors and leads to activation of the pro-survival canonical NF-kB and the c-Jun N-terminal kinase (JNK) cascades or the secondary apoptotic cascade through the complex II [46].

Early studies of TNFRI internalization showed that upon TNFa stimulation, TNFR1 was internalized [49] and did not undergo recycling [50]. Although early data of electron microscopy suggested that TNFRI could enter the cell via clathrin-coated pits [51], subsequent studies showed that it is internalized through caveolae or lipid rafts [52-54]. Upon TNFa stimulation, TNFR1 co-localized with caveolin in cholesterol-rich lipid domains, but not with clathrin-coated pits [53].

The cholesterol- and sphingolipid-enriched membrane microdomains were shown as sites of TNFR1 ubiquitylation and recruitment of signaling molecules from complex I, while inhibition of endocytosis by several chemical agents partly perturbed both TNF uptake as well as TNF-induced gene activation [52,55]. These pieces of evidence argue for requirement of endocytosis in TNF signaling. In addition, lipid raft disruption was shown to block IkBa phosphorylation and to sensitize cells to TNFa-induced apoptosis [52], suggesting that TNFRI requires redistribution to lipid rafts to induce the NF-kB response, but not apoptosis. The study of Schneider-Brachert et al. supported this view, as they proposed that the initial TNFR1 signaling through the complex I (NF-kB and c-Jun pathways) is independent of receptor internalization and therefore originates from the plasma membrane, whereas assembly of complex II was linked to receptor internalization suggesting endosomal origin of the pro-apoptotic signaling events [56].

Consistently with this model, D'Alessio et al. showed that cholesterol depletion with methyl-b-cyclodextrin (MbCD) reduced receptor internalization but did not inhibit TNF-induced NF-kB pathway [53]. Their next study showed that silencing of caveolin-1 or flotilin-2 did not affect the NF-kB activation [54]. Strikingly, caveolin silencing not only did not block internalization of the receptor, but resulted in its redistribution to the early endosomes [54]. Possibly, TNFRI relocates to lipid rafts after stimulation but it can signal to NF-kB both from the plasma membrane microdomains and outside of them. Meanwhile, as TNFR1 internalization only partially depends on lipid rafts, the endosomal proapoptotic signaling can take place even when the plasma membrane cholesterol-rich microdomains are perturbed. The notion that TNFa-induced MAPK signaling originated from the plasma membrane was also confirmed by evidence that inhibiting dynamin function potentiated JNK and p38 phosphorylation induced by TNFa and enhanced TNFa-induced physiological responses [57].

The model of TNFR1-related compartmentalization of pro-survival and death-inducing signaling cascades proposed by Schneider-Brachert et al. has been expanded by their next studies suggesting that the internalized receptor is sorted to the interior of MVBs, where the pro-apoptotic signal is amplified through action of acid sphingomyelinase (ASMase) [56,58-60]. However, this is in conflict with the current knowledge of the receptor topology inside the multivesicular bodies, as discussed elsewhere [61]. A complementary mechanism of apoptotic signal transduction from the surface of MVBs was proposed to involve protein Alix (ALG-2 interacting protein X; PDCD6IP). Alix associates with the membranes and the ESCRT machinery when activated by calcium-

binding ALG-2 (PDCD6) [62,63], and regulates MVB biogenesis and EGFR sorting [64,65]. The work of Mahul-Mellier and colleagues [66] provided evidence, that Alix and ALG-2 can form a complex with pro-caspase 8 and TNFR1 on endosomes, thereby mediating TNF-induced apoptosis downstream of the receptor internalization. Alix binding to TNFRI depended on association with ESCRTs, underscoring the role of MVBs in signal propagation. The same study also confirmed that TNFRI internalization and TNFRI-induced cell death depended on activity of dynamin 2, supporting the model for apoptotic signaling originating from endosomes.

The relation of TNFRI signaling and endocytosis is one of the best studied among cytokine receptors. It is well established, that TNF-induced apoptotic signaling requires endocytosis and endosomal machinery. Still, the receptor most probably uses many internalization mechanisms but it is unclear what their exact identity is and how they affect the signaling output.

2.2. Death receptors (DRs)

The spatial separation of apoptosis and non-death signaling pathways seems to function also for the death receptor CD95 (Fas). This is the prototypical death-inducting receptor, mainly studied in the context of Fas ligand (FasL)-induced apoptosis. CD95 is rapidly clustered and internalized (within 3-15 min) upon stimulation with a soluble or transmembrane ligand, simultaneously inducing apoptotic signaling [67,68]. Although association of the receptor with the death-inducing signaling complex (DISC) elements such as FADD and caspase 8 seemed to precede its internalization, the DISC formation peaked at 30 min and depended on receptor internalization. Interestingly, CD95 was shown to co-exist with Rab4 and EEA1 in isolated receptosomes, suggesting that CD95 undergoes recycling towards the plasma membrane [68]. This could potentially prolong CD95 signaling but also increase its dependence on internalization. Importantly, blocking CD95 cell entry inhibited apoptosis but enabled activation of NF-kB and ERK1/2 [68]. The mechanisms of CD95 endocytosis seem to involve its palmitoylation and enrichment in lipid rafts, which are needed for induction of apoptosis [69-71]. Although this may point to clathrin-independent internalization routes, several reports suggest that CD95 endocytosis depends on actin cytoskeleton and its regulator ezrin, but also partially on clathrin and dynamin [70,7275]. Involvement of these three elements may indicate that CD95 uses several cell entry routes, but their functional interconnections remain unclear.

TRAIL receptor is also a well-studied inducer of apoptosis, however its endocytosis is poorly defined and most probably various internalization mechanisms play a role in this process. Receptors for the TRAIL ligand are also known as death receptors (DR3, 4, 5, 6), where TRAILR1 (DR4) and TRAILR2 (DR5) are signaling receptors, while DR3 and DR6 are decoy receptors. The induced TRAILR2 was localized in electron-dense plasma membrane invaginations resembling clathrin-coated pits [76] and internalization of the TRAIL ligand depended on dynamin and clathrin adaptor AP180C, but a fraction of the receptor was also internalized via dynamin-independent mechanisms [77]. The later fate of the receptor is assumed to involve its degradation. It was suggested that TRAILR2 is directed to lysosomes where it continues to signal and promotes release of lysosomal proteases to induce apoptosis [78].

The requirement of endocytosis inTRAILR2 receptor signaling is under debate, as it was shown to be both required [78] and dispensable [77] for apoptotic signaling. According to Akazawa et al. [78], dominant-negative mutant of dynamin 2 and silencing of Rab7 inhibit apoptotic signaling induced by TRAILR2, which suggests that both early and late trafficking events are needed for signal propagation. Interestingly, prolonged TRAIL treatment


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(minimum 1 h) interferes with the endocytic machinery by caspase-dependent cleavage of clathrin and its adaptor AP2 [76], but the initial internalization rate of TRAIL occurs within minutes and should not be affected by these proteolytic events.

Cumulatively, internalization of CD95 and TRAIL death receptors is most likely required for their proapoptotic signaling.

2.3. Non-death TNFR superfamily receptors

The interplay of endocytosis and signaling of non-death TNFR superfamily receptors is relatively poorly studied, with LTbR and CD40 being few known examples. Both receptors exert their function through activation of the canonical and noncanonical NF-kB pathways. In vivo these receptors are activated by membrane-bound ligands exposed on the surfaces of lymphocytes [79,80].

LTbR does not possess a death domain, but contains TRAF-binding sites that can interact with TRAF2, 3, 4 and 5 [81-83]. The recruitment of TRAF2/5 to the LTbR tail induces the canonical pathway, whereas binding of TRAF2 and TRAF3 activates the noncanonical NF-kB branch. Importantly, spatial segregation of TRAF protein pools associated with the receptor in each pathway was proposed to facilitate separation of the two signaling cascades [84]. Activation of the noncanonical NF-kB pathway was shown to rely on dynamin-dependent internalization of LTbR, whereas the canonical branch was not affected by blocking clathrin or dynamin activities. Thus, similarly to TNFR1, the canonical NF-kB pathway may be induced by LTbR at the plasma membrane, while secondary signaling, in this case the noncanonical NF-kB, requires endocytosis. The work of Ganeff et al. [84] offers an attractive model for the separation of the two NF-kB signaling cascades by spatial distribution of the receptor along with its adaptors, but details of this regulation remain elusive and need further studies.

Endosomal signaling of LTbR is also possible in a ligand-independent manner. Our recent work showed that depletion of ESCRT components Tsg101, Vps28, UBAP1 (ESCRT-I) or CHMP4B (ESCRT-III) leads to ligand-independent induction of the canonical and noncanonical NF-kB pathway [85]. This activation strongly depended on LTbR and TNFRI, which accumulated on enlarged early endosomes and were activated independently of TNFa, lymphotoxin or serum-derived ligands. Our results suggest that cytokine receptors undergo constitutive internalization and on endosomes can be sorted by ESCRTs towards lysosomal degradation. By this means the endocytic system could serve as a potent guardian preventing spurious, ligand-independent signaling. It remains an open question whether ligand-independent LTbR signaling from endosomes activates both NF-kB branches or just the noncanonical one.

Similarly to LTbR, CD40 can activate the canonical and noncanonical NF-kB pathways but also signaling dependent on p38, Akt, JNK and STAT5 [79,86,87]. The CD40 receptor is expressed on antigen presenting cells (APCs), both professional such as B cells, macrophages, dendritic cells as well as non-professional like endothelial cells, vascular smooth muscle cells and fibroblasts. The CD40 molecule can be activated by a transmembrane ligand present on T lymphocytes or its soluble counterpart shed from platelets [79].

It is well established that CD40 becomes enriched within lipid rafts and forms clusters in different cell types after induction with the transmembrane ligand CD40L (CD154) or agonistic antibodies [88-90]. Lipid rafts were also shown to be essential for CD40 ligand clustering [91], recruitment of adaptors TRAF2 and TRAF3 [90,92] and for phosphorylation of Akt, but not p38 or JNK, upon CD40 stimulation [93]. Interestingly, ceramide produced by acid sphingomyelinase (ASMase) was necessary to drive CD40 ligand clustering on the plasma membrane and to induce subsequent IL-

12 production after treatment of lymphocytes with agonistic antibodies [89]. Although involvement of lipid rafts in CD40 clustering is well documented, the mechanisms of receptor internalization or its trafficking routes remain obscure. Two studies attempted to address these questions, but the data obtained with overexpressed receptor were difficult to interpret [94,95].

3. IL-1 superfamily receptors

The IL-1 receptor (IL-1R) superfamily contains several transmembrane protein complexes including 4 signaling receptors, IL-1, IL-18, IL-33 and IL-36 receptors [96]. The best studied among this group, IL-1R, is present predominantly on the surface of B- and T-lymphocytes and macrophages but also of fibroblasts and many other cell types. Upon binding of IL-1, IL-1R1 undergoes conformational changes and forms a heterodimer with the accessory protein, IL-1RAcP. Then both subunits bind MyD88 proteins via their Toll/IL-1 receptor (TIR) domain. Subsequently, MyD88 recruits the IL-1R-associated kinases, IRAK1 and IRAK4. Reciprocal interactions and phosphorylation events lead to dissociation of IRAK1 from the complex and its binding to TRAF6 which then activates the canonical NF-kB pathway.

IL-1R1 was shown to undergo constitutive turnover through the endolysosomal system that is increased upon ligand binding [97]. IL-1R1 degradation requires the Tollip protein that binds ubiq-uitylated receptor and mediates its sorting to late endosomes and lysosomes [98]. IL-1R relocalized to lipid fractions enriched in caveolin-1 upon binding IL-1 in primary rat astrocytes [99], however it is not clear whether cellular entry of this receptor requires caveolin-1 or cholesterol. In fact, the dependence of IL-1-induced signaling on receptor internalization may be limited to several specific signaling events. In the current model, activation of IL-1-induced NF-kB signaling cascade proceeds from the plasma membrane independently of receptor internalization, however additional signaling events that required endocytosis were shown to be necessary for full NF-kB transcriptional response [100]. In more detail, inhibiting dynamin function did not affect p50:RelA nuclear translocation nor its binding to DNA, but it partially impaired IL-1-induced activation of NF-kB target genes [100]. A follow-up study revealed that the endocytic route of IL-1R required activation of small GTPase Rac1 [101]. These data are consistent with the finding that overexpression of the dynamin dominantnegative mutant or knock-down of Rac1 only partially (both by ~50%) inhibited NF-kB luciferase reporter activity upon IL-1 induction [102].

Both IL-1 and IL-1R proteins contain putative nuclear localization sequences (NLS) and were found in the cell nucleus [97,99,103,104]. Consistently, known IL-1R adaptors, IRAK1 and phosphoinositide 3-kinase (PI3K), were reported to translocate to the nucleus in an IL-1-dependent manner [105,106]. Potential nuclear translocation of IL-1R has never been excluded and could possibly be a consequence of the above mentioned Rac1-dependent endocytosis of this receptor [101].

Endocytic trafficking was investigated for IL-36R, another member of the IL-1 superfamily. Its signaling shares common features with that of IL-1R. Although having a distinct ligand-specific subunit (IL-1Rrp2, also known as IL-1R6), this receptor also interacts with the accessory IL-1RAcp protein [107]. Upon binding of the ligand (IL-36 a, b or g), the two proteins interact and activate signaling cascades similar to those of IL-1. Ligand-induced IL-36R co-localized with clathrin, an established clathrin-depen-dent cargo transferrin and to a lesser extent with a clathrin-independent cargo, cholera toxin [108]. This suggests that IL-36R is internalized by several endocytic routes with preference towards CME.


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4. IL receptors containing the common gamma chain (gc)

The common gamma chain (gc, CD132) is a subunit of heterodimeric or heterotrimeric receptors that bind interleukins IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Among them are two receptors IL-2R and IL-15R that consist of three different subunits with specific functions. The gc is responsible for signal transduction, the a chain confers ligand specificity, while b subunit (present only in IL-2R and IL-15R) participates in both events [109]. Upon ligand recognition, the dispersed subunits come together and the gc recruits JAK3 tyrosine kinase which phosphorylates and activates STAT transcription factors. Although different STAT molecules are activated by these cytokines, IL-2, IL-7, IL-9, and IL-15 predominantly signal through STAT5, while IL-4 acts mainly through STAT6, and IL-21 through STAT3 and STAT1 [110,111].

The studies describing endocytosis of the gc showed that it undergoes constitutive internalization followed by lysosomal degradation [112]. The gc chain ectopically expressed in HeLa cells in the absence of any ligand underwent CIE which required dynamin, cortactin and actin polymerization [113].

Many receptors from this group undergo CIE, with IL-2R being characterized to the highest extent. Early studies showed that IL-2R is internalized and degraded in a constitutive manner [114], but its decay can be accelerated by high concentrations of IL-2 [115]. The distinction between these two modes of internalization is attributed to different regions of gc chain cytoplasmic tail, where slow, constitutive trafficking requires membrane-proximal amino acids and the rapid, IL-2-induced internalization depends on residues distal to the transmembrane region [116]. It is therefore possible that gc subunit may use distinct sorting signals for its constitutive regulation and ligand-induced endocytosis.

Despite joint internalization of all IL-2R subunits, in the later steps the a chain was shown to be transported independently of other chains, being directed to transferrin-positive structures, most likely early recycling endosomes, while never reaching lysosomes [117]. This is consistent with a relatively high stability of the a chain. Conversely, b and g chains reached Rab7-positive compartment and were rapidly degraded [117].

IL-2R is one of the first signaling receptors described to undergo CIE [118]. Its internalization occurs in detergent-resistant microdomains (DRMs) of the plasma membrane and requires dynamin as well as proteins that regulate actin polymerization, namely phosphoinositide kinase PI3K, Rho GTPase Rac1, its guanine nucleotide exchange factor (GEF) Vav2, kinases Pak1 and Pak2, endocytic adaptor cortactin, and Arp2/3 stimulator N-WASP [13,119-121]. PI3K plays a central role in IL-2R internalization. Its regulatory subunit p85 associates with IL-2-R(b) and activates the recruitment of its catalytic p110 subunit to produce phospha-tidylinositol (3,4,5)-trisphosphate. This induces Vav2 to activate GTPase Rac1, which is then recruited to IL-2R-bound p85 subunit of PI3K and stimulates Pak kinases. They promote local actin polymerization through cortactin and N-WASP [119]. These events likely occur at the last step of internalization, namely the vesicle scission from the plasma membrane. A recent electron microscopy- and tomography-based study shed light on earlier events of IL-2R endocytosis [122]. The authors propose a model in which IL-2Rb internalization is initiated at the basis of membrane protrusions, where internalization pits form and invaginate adjacently to the base of the protrusion, thanks to the sequential action of outward and inward forces created by actin polymerizing machinery WAVE, N-WASP and cortactin. The scission of a newly formed vesicle is performed by dynamin. In agreement, IL-2R was identified among cargoes of a recently characterized clathrin-independent endocytic route, termed fast endophilin-mediated endocytosis (FEME), which likewise requires dynamin, Rac, PI3K, PAK1 and actin polymerization and occurs at sites of formation of

protrusive lamellipodia (at the leading edge of migrating cells) [15]. Thus, the mechanisms of IL-2R endocytosis are quite well understood, however its role in regulation of downstream signaling is less known.

The interrelation between endocytosis and signaling was in turn studied in the case of IL-4R. Biophysical analysis pointed out that endogenous concentrations of IL-4Ra and common gc subunits on the plasma membrane are too low for efficient dimerization which implies the existence of a concentration mechanism that must occur for IL-4 signal transduction [123]. It was proposed that newly formed endocytic structures (specifically termed cortical endosomes, as they are close to cellular actin cortex) allow the subunits to concentrate on their membranes, dimerize and initiate JAK3-mediated signaling. Similarly to IL-2R endocytosis, the formation of IL-4R-concentrating cortical endo-somes was mediated by Rac1/Pac signaling towards actin polymerization [124]. Another similarity in endocytosis of IL-2 and IL-4 receptors is that their subunits (specifically IL-2Rb and IL-4Ra) contain a hydrophobic amino acid cluster that is recognized early after ligand stimulation. It is hence possible that, similarly to IL-4R, endocytosis of IL-2R provides membrane environment that facilitates concentration of receptor subunits.

5. IL receptors containing the common beta chain (pc)

IL-3, IL-5 cytokines and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) are important for hematopoiesis, regulating myeloid differentiation and function, but are also involved in inflammatory and allergic responses [125]. The high affinity receptors for these ligands are heterotrimers composed of a ligand-specific a chain and a dimer of shared common chain bc. The a chain alone has a weak ligand binding affinity but it is strongly increased upon association with the common chain [126]. In addition, bc plays a major role in transmitting ligand-activated downstream signals, which involves JAK-STAT, Ras-MAPK, and PI3K pathways. In human, IL-3R and the GM-CSF receptors are expressed in multipotent as well as lineage-committed myeloid progenitors, and IL-5R is mainly present on eosinophils and basophils [125,127].

Endocytosis of the bc-containing IL receptors is not extensively described, although studies that focused on IL-5R in human eosinophils and TF-1 leukemia cells shed some light on this subject. As shown in these models, endocytosis of IL-5R was required for its signaling. Stimulation with IL-5 leads to the receptor activation, ubiquitylation, internalization and lysosomal degradation [128]. As proposed, IL-5R can be internalized via both clathrin- and lipid raft-dependent endocytosis [128,129], however further experiments involving depletion of specific endocytic regulators need to be performed to verify this notion. The phosphorylated and ubiquitylated receptor partitioned to the detergent-soluble, non-raft membrane fractions and unspecific inhibition of endocytosis prevented receptor association with downstream signaling molecules [129]. Consistently, overex-pressed ubiquitylation-deficient IL-5R accumulated on the cell surface and had impaired signaling capability [130]. Although the function of specific endocytic routes is still not clear, it is well documented that IL-5R requires endocytosis for its signaling.

The bc chain plays an important role both in IL-5R endocytosis and signaling. Upon IL-5 stimulation, the cytosolic part of the bc chain was shown to be proteasomally cleaved as a prerequisite for endolysosomal degradation of the whole receptor complexes [131]. This processing required tyrosine phosphorylation of the receptor by JAK1 and JAK2 kinases and occurred after the internalization [128]. Importantly, the inhibition of bc proteasomal cleavage delayed lysosomal degradation of the receptor, at the same time prolonging the JAK-STAT signaling. This leads to an


J. Cendrowski et al./Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx 7

attractive hypothesis that the timing of the bc cleavage might serve as a way to regulate the duration of IL-5R receptor signaling from endosomal compartments.

6. IL receptors containing the common gp130 chain

Receptors for cytokines from the IL-6 family (IL-6, IL-11, LIF, OSM, CNTF, and CT1) share a common gp130 subunit [132]. They form heterodimers or heterotrimers that involves one or two gp130 molecules. Within this family, the endocytosis is best described for IL-6R. The IL-6 cytokine is produced by and acts on various cell types, mediating inflammation, cell proliferation and differentiation [133]. The receptor for IL-6 is a heterotrimer consisting of one ligand-specific IL-6Ra and two gp130 subunits that oligomerize upon IL-6 binding and activate the JAK-STAT and MAPK pathways [134,135]. Regarding STAT proteins, IL-6 predominantly acts through STAT3 and to a lesser extent via STAT1 [136].

The IL-6 receptor was shown to undergo ligand-independent, constitutive internalization which did not require activation of the JAK-STAT pathway [137,138]. IL-6 increased the rate of receptor internalization and lysosomal degradation [139,140] mediated by c-CBL-driven monoubiquitylation of gp130. The monoubiquitin tag was recognized by Hrs, which sorts activated receptors towards lysosomal degradation [139].

The internalization route of gp130 is under debate, with reported constitutive association with the AP-2 complex [137] or with caveolae [141]. Further studies provided more evidence in favor of CIE. The gp130 was found in caveolin-1-positive lipid rafts regardless of ligand stimulation [142]. Interestingly, these rafts also contained non-phosphorylated STAT3 molecules that underwent phosphorylation upon IL-6 treatment. Consistently, cholesterol-sequestering agent MbCD inhibited IL-6-induced STAT3\ DNA binding [142], while caveolin-1 depletion in human fibroblasts impaired IL-6-induced MAP kinase signaling [143]. Another study found that upon IL-6 stimulation STAT3 became phosphorylated on early endosomes from where it subsequently translocated to the nucleus [144]. This interaction of STAT3 with

endosomes was transient and once phosphorylated, STAT3 relocated to the nucleus in a manner not dependent on endocytic trafficking.

Collectively, these data suggest that STAT3 can spontaneously bind to gp130-containing receptors both on the plasma membrane and early endosomes but once it becomes phosphorylated it dimerizes and translocates to the nucleus leaving the receptors free to bind subsequent STAT3 molecules. This allows the signal propagation as long as the JAK-bound cytoplasmic tails are exposed, which is terminated for instance upon sequestration into ILVs.

7. Interferon receptors

Interferons (IFNs) are key mediators of innate and acquired antiviral response and negatively regulate proliferation of cancer cells. IFNs of type I (a, b, k, v, t) and type II (only g) are distinguished. Type I IFNs transmit their signals through IFNAR heterodimeric receptor (composed of IFNAR1 and IFNAR2 sub-units), while IFN-g binds and activates IFNGR receptor dimers (IFNGR1 and IFNGR2). IFN-induced signaling is propagated through the JAK-STAT pathway [145]. Activated IFNAR recruits STAT2, which upon phosphorylation binds STAT1 and allows for its phosphorylation [146], while IFNGR signals only through STAT1 homodimers [147]. Both IFNAR and IFNGR were initially described to associate with caveolin-positive membrane microdomains [148] which suggested that at least a fraction of the IFN receptors could be internalized via lipid rafts.

Endocytosis of IFNAR and IFNGR was thoroughly investigated by Lamaze and colleagues who showed that in HeLa cells, upon ligand binding both receptors undergo clathrin- and dynamin-dependent endocytosis [149]. In this study, inhibiting dynamin function or silencing clathrin abrogated IFN-a-induced STAT signaling as well as antiviral and antiproliferative activities of IFN-a. In contrast, these conditions had no effect on IFNGR signaling and function. Instead, IFN-g binding led to rapid relocalization of a significant fraction of its receptor to DRMs

Fig. 2. Cytokine receptors signal from the plasma membrane and endosomes. Ligand-activated signaling of cytokine receptors can be regulated by endocytosis. Induction of the NF-kB or JNK signaling cascades by 1L-1R and the listed TNFRSF receptors occurs at the plasma and is internalization-independent. Conversely, apoptotic, non-canonical NF-kB or JAK-STAT pathways downstream of death receptors, LT|3R or 1LRs/1FNAR, respectively, require receptor internalization and are activated from endosomal compartment (signaling endosomes). Many ILRs, IFNAR, and possibly TNFR1 and LT|3R, undergo ligand-induced, lysosomal degradation while there is very little evidence for recycling of cytokine receptors.


8 J. Cendrowski et al./Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx

and the receptor activation was found to be dependent on availability of membrane cholesterol. This is consistent with earlier findings showing that IFNGR1 localized in caveolin-1 positive DRMs and that cholesterol sequestration inhibited IFN-g-induced STAT1 signaling [142,150]. Collectively, these data show that type I and II IFN receptors have distinct modes of activation. IFNAR signaling requires clathrin- and dynamin-mediated inter-nalization that allows for recruitment of signaling adaptors and eventual signal termination that was confirmed by subsequent studies [151,152]. Conversely, IFNGR requires lipid rafts for its signaling but it was not verified whether ligand-activated IFNGR can internalize from these microdomains. Possibly, such lipid environment could allow for selective endocytosis and the proposed nuclear translocation of IFN-g-bound IFNGR1 [150,153], however this hypothesis is still to be addressed.

8. Perspectives

Biology of cytokine receptors is very complex as they induce diverse signaling pathways and outputs which vary depending on the cellular context, concentration and duration of exposure to a ligand, as well as crosstalk with simultaneous stimuli. Understanding endocytic mechanisms of cytokine receptors could clarify some of these complicated relations.

The data presented in this review underscore an important role of endocytic internalization in biology of various cytokine receptors. Moreover, in several cases endosomes may serve as intracellular signaling platforms for these receptors (Fig. 2). The NF-kB and JAK-STAT signaling pathways involve cytosolic adaptors which are available to be recruited both at the plasma membrane and on intracellular endosomes. Thus, the same signaling events that take place at the plasma membrane can continue or repeat in multiple cycles during receptor trafficking until its sequestration in the ILVs, as exemplified by IL-6R-dependent activation of STAT3. In the case for TNFR1 or LT^R, ligand-induced activation of the canonical NF-kB pathway occurs at the plasma membrane and is not affected by endocytosis inhibition, whereas the secondary signaling events (apoptosis and the noncanonical NF-kB pathway, respectively) strongly depend on internalization and signaling from endosomes. In addition, our study showed that receptors such as TNFR1 or LT^R may spontaneously oligomerize and activate the NF-kB pathway from endosomes in a ligand-independent manner upon trafficking block that facilitates accumulation of cargo on the endosomes [85]. Such mechanism may also occur in case of unperturbed endocytosis: ligand-stimulated IL-4R exclusively requires internalization for signal propagation as endosomal concentration of the receptor subunits favors their dimerization. These data underline the property of endosomes to enable local clustering of trafficked cargo thanks to their limited size and confined membrane space.

Overall, with few exceptions, interrelation between endocytosis and signaling of cytokine receptors is poorly studied. IL-2R is very thoroughly examined with respect to its internalization, although is still to be discovered whether it requires endocytosis for signaling. In contrast, such endocytic requirement for signaling has been shown for IFNa receptor but without unraveling its molecular mechanisms. As IFNAR differs from IL-4R in terms of signaling adaptors and internalization route, it may use other mechanisms of signal modulation, rather than the endosomal concentration described above.

Collectively, two complementary approaches still need to meet to understand the regulation of signaling initiated by cytokine receptors. On the one hand, we require much more detailed information about endocytic mechanisms used by cytokine receptors. On the other hand, we should know better how signaling complexes are formed in space and time. Despite fast

progress of knowledge about types of internalization mechanisms, data regarding endocytosis of most cytokine receptors are still fragmentary. Several of these receptors were only shown to use lipid rafts for signaling, but without information if they internalize through this portal and what the potential CIE route used would be. Only when knowing this, one could try to determine if cytokine receptors also use different internalization routes to activate different signaling cascades, as exemplified by EGFR. Next, data showing how the balance between recycling and degradation is maintained could help to locate the signaling complexes in the subcellular compartments. This is also true for noninduced receptors that undergo constitutive internalization such as IL-1R, IL-2R, IL-6R, and possibly TNFRI, LT^R and gp130-containing receptors. Internalization mechanisms can be cell type specific, for example some CIE routes take place preferentially during cell migration. Possibly, hematopoietic and non-hematopoietic cells bearing cytokine receptors can be specialized towards particular internalization and trafficking routes. Verifying and understanding these properties could greatly improve our understanding of biology of cytokine receptors.


Work in the authors laboratory is supported by a grant from Switzerland through the Swiss Contribution to the enlarged European Union (Polish-Swiss Research Programme project PSPB-094/2010), by a MAESTRO grant (UMO-2011/02/A/NZ3/00149) from National Science Center and by the EU FP7 grant FishMed GA No. 316125 to M.M.


[1] E. Barbieri, P.P. Di Fiore, S. Sigismund, Endocytic control of signaling at the plasma membrane, Curr. Opin. Cell Biol. 39 (2016) 21-27.

[2] A. Tomas, C.E. Futter, E.R. Eden, EGF receptor trafficking: consequences for signaling and cancer, Trends Cell Biol. 24 (2014) 26-34.

[3] A. Marchese, Endocytic trafficking of chemokine receptors, Curr. Opin. Cell Biol. 27 (2014) 72-7 .

[4] M. Miaczynska, Effects of membrane trafficking on signaling by receptor tyrosine kinases, Cold Spring Harb. Perspect. Biol. 5 (2013) a009035.

[5] N.G. Tsvetanova, R. Irannejad, M. von Zastrow, G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins from endosomes, J. Biol. Chem. 290 (2015) 6689-6696.

[6] H.T. McMahon, E. Boucrot, Molecular mechanism and physiological functions of clathrin-mediated endocytosis, Nat. Rev. Mol. Cell Biol. 12 (2011) 517-533.

[7] T. Kirchhausen, D. Owen, S.C. Harrison, Molecular structure, function, and dynamics of clathrin-mediated membrane traffic, Cold Spring Harb. Perspect. Biol. 6 (2014) a016725.

[8] E. Cocucci, R. Gaudin, T. Kirchhausen, Dynamin recruitment and membrane scission at the neck of a clathrin-coated pit, Mol. Biol. Cell 25 (2014) 3595-3609.

[9] S. Mayor, R.G. Parton, J.G. Donaldson, Clathrin-independent pathways of endocytosis, Cold Spring Harb. Perspect. Biol. 6 (2014).

[10] P. Drevot, C. Langlet, X.J. Guo, A.M. Bernard, O. Colard, J.P. Chauvin, et al., TCR signal initiation machinery is pre-assembled and activated in a subset of membrane rafts, EMBO J. 21 (2002) 1899-1908.

[11] R.G. Parton, J.F. Hancock, Lipid rafts and plasma membrane microorganization: insights from Ras, Trends Cell Biol. 14 (2004) 141-147.

[12] M. Bastiani, R.G. Parton, Caveolae at a glance, J. Cell Sci. 123 (2010) 3831-3836.

[13] C. Lamaze, A. Dujeancourt, T. Baba, C.G. Lo, A. Benmerah, A. Dautry-Varsat, Interleukin 2 receptors and detergent-resistant membrane domains define a clathrin-independent endocytic pathway, Mol. Cell 7 (2001) 661-671.

[14] H.F. Renard, M. Simunovic, J. Lemiere, E. Boucrot, M.D. Garcia-Castillo, S. Arumugam, et al., Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis, Nature 517 (2015) 493-496.

[15] E. Boucrot, A.P. Ferreira, L. Almeida-Souza, S. Debard, Y. Vallis, G. Howard, et al., Endophilin marks and controls a clathrin-independent endocytic pathway, Nature 517 (2015) 460-465.

[16] S. Sabharanjak, P. Sharma, R.G. Parton, S. Mayor, GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway, Dev. Cell 2 (2002) 411-423.

[17] M. Kirkham, A. Fujita, R. Chadda, S.J. Nixon, T.V. Kurzchalia, D.K. Sharma, et al., Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles, J. Cell Biol. 168 (2005) 465-476.


J. Cendrowski et al./Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx

[18] R. Lakshminarayan, C. Wunder, U. Becken, M.T. Howes, C. Benzing, S. Arumugam, et al., Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers, Nat. Cell Biol. 16 (2014) 595-606.

[19] S. Kumari, S. Mayor, ARF1 is directly involved in dynamin-independent endocytosis, Nat. Cell Biol. 10 (2008) 30-41.

[20] Y. Egami, T. Taguchi, M. Maekawa, H. Arai, Araki N. Small, GTPases and phosphoinositides in the regulatory mechanisms of macropinosome formation and maturation, Front. Physiol. 5 (2014) 374.

[21] C. Bucci, R.G. Parton, I.H. Mather, H. Stunnenberg, K. Simons, B. Hoflack, et al., The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway, Cell 70 (1992) 715-728.

[22] M. Miaczynska, S. Christoforidis, A. Giner, A. Shevchenko, S. Uttenweiler-Joseph, B. Habermann, et al., APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment, Cell 116 (2004) 445-456.

[23] I. Kalaidzidis, M. Miaczynska, M. Brewinska-Olchowik, A. Hupalowska, C. Ferguson, R.G. Parton, et al., APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments, J. Cell Biol. 211 (2015) 123-144.

[24] P. van der Sluijs, M. Hull, P. Webster, P. Male, B. Goud, I. Mellman, The small GTP-binding protein rab4 controls an early sorting event on the endocytic pathway, Cell 70 (1992) 729-740.

[25] O. Ullrich, S. Reinsch, S. Urbe, M. Zerial, R.G. Parton, Rab11 regulates recycling through the pericentriolar recycling endosome, J. Cell Biol. 135 (1996) 913-924.

[26] M. Zerial, H. McBride, Rab proteins as membrane organizers, Nat. Rev. Mol. Cell Biol. 2 (2001) 107-117.

[27] C. Raiborg, H. Stenmark, Hrs and endocytic sorting of ubiquitinated membrane proteins, Cell Struct. Funct. 27 (2002) 403-408.

[28] K.G. Bache, C. Raiborg, A. Mehlum, H. Stenmark, STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes, J. Biol. Chem. 278 (2003) 12513-12521.

[29] C. Raiborg, T.E. Rusten, H. Stenmark, Protein sorting into multivesicular endosomes, Curr. Opin. Cell Biol. 15 (2003) 446-455.

[30] J. Gruenberg, The endocytic pathway: a mosaic of domains, Nat. Rev. Mol. Cell Biol. 2 (2001) 721-730.

[31] J. Rink, E. Ghigo, Y. Kalaidzidis, M. Zerial, Rab conversion as a mechanism of progression from early to late endosomes, Cell 122 (2005) 735-749.

[32] J.P. Luzio, B.A. Rous, N.A. Bright, P.R. Pryor, B.M. Mullock, R.C. Piper, Lysosome-endosome fusion and lysosome biogenesis, J. Cell Sci. 113 (Pt. 9) (2000) 1515-1524.

[33] J.P. Luzio, P.R. Pryor, N.A. Bright, Lysosomes: fusion and function, Nat. Rev. Mol. Cell Biol. 8 (2007) 622-632.

[34] J.P. Luzio, Y. Hackmann, N.M. Dieckmann, G.M. Griffiths, The biogenesis of lysosomes and lysosome-related organelles, Cold Spring Harb. Perspect. Biol. 6 (2014).

[35] A. Yu, J.F. Rual, K. Tamai, Y. Harada, M. Vidal, X. He, et al., Association of dishevelled with the clathrin AP-2 adaptor is required for frizzled endocytosis and planar cell polarity signaling, Dev. Cell 12 (2007) 129-141.

[36] R.H. Oakley, S.A. Laporte, J.A. Holt, L.S. Barak, M.G. Caron, Association of beta-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization, J. Biol. Chem. 274 (1999) 32248-32257.

[37] K.A. DeFea, J. Zalevsky, M.S. Thoma, O. Dery, R.D. Mullins, N.W. Bunnett, Beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2, J. Cell Biol. 148 (2000) 1267-128 .

[38] S.M. DeWire, S. Ahn, R.J. Lefkowitz, S.K. Shenoy, Beta-arrestins and cell signaling, Annu. Rev. Physiol. 69 (2007) 483-510.

[39] R. Irannejad, J.C. Tomshine, J.R. Tomshine, M. Chevalier, J.P. Mahoney, J. Steyaert, et al., Conformational biosensors reveal GPCR signalling from endosomes, Nature 495 (2013) 534-538.

[40] J.M. Gaullier, A. Simonsen, A. D'Arrigo, B. Bremnes, H. Stenmark, R. Aasland, FYVE fingers bind Ptdlns(3)P, Nature 394 (1998) 432-433.

[41] S. Hayes, A. Chawla, S. Corvera, TGF beta receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2, J. Cell Biol. 158 (2002) 1239-1249.

[42] Y.G. Chen, Z. Wang, J. Ma, L. Zhang, Z. Lu, Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signaling, J. Biol. Chem. 282 (2007) 9688-9695.

[43] N. Nakamura, J.R. Lill, Q. Phung, Z. Jiang, C. Bakalarski, A. de Maziere, et al., Endosomes are specialized platforms for bacterial sensing and NOD2 signalling, Nature 509 (2014) 240-244.

[44] S. Sigismund, E. Argenzio, D. Tosoni, E. Cavallaro, S. Polo, P.P. Di Fiore, Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation, Dev. Cell 15 (2008) 209-219.

[45] J. Li, Q. Yin, H. Wu, Structural basis of signal transduction in the TNF receptor superfamily, Adv. Immunol. 119 (2013) 135-153.

[46] O. Micheau, J. Tschopp, lnduction of TNF receptor l-mediated apoptosis via two sequential signaling complexes, Cell 114 (2003) 181-190.

[47] W. Schneider-Brachert, U. Heigl, M. Ehrenschwender, Membrane trafficking of death receptors: implications on signalling, Int. J. Mol. Sci. 14 (2013) 14475-14503.

[48] V. Tchikov, U. Bertsch, J. Fritsch, B. Edelmann, S. Schutze, Subcellular compartmentalization of TNFreceptor-1 and CD95 signaling pathways, Eur. J. Cell Biol. 90 (2011) 467-475.

[49] M. Higuchi, B.B. Aggarwal, TNF induces internalization of the p60 receptor and shedding of the p80 receptor, J. Immunol. 152 (1994) 3550-3558.

[50] N. Watanabe, H. Kuriyama, H. Sone, H. Neda, N. Yamauchi, M. Maeda, et al., Continuous internalization of tumor necrosis factor receptors in a human myosarcoma cell line, J. Biol. Chem. 263 (1988) 10262-10266.

[51] R. Mosselmans, A. Hepburn, J.E. Dumont, W. Fiers, P. Galand, Endocytic pathway of recombinant murine tumor necrosis factor in L-929 cells, J. lmmunol. 141 (1988) 3096-3100 .

[52] D.F. Legler, O. Micheau, M.A. Doucey, J. Tschopp, C. Bron, Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation, lmmunity 18 (2003) 655-664.

[53] A. D'Alessio, R.S. Al-Lamki, J.R. Bradley, J.S. Pober, Caveolae participate in tumor necrosis factor receptor 1 signaling and internalization in a human endothelial cell line, Am. J. Pathol. 166 (2005) 1273-1282.

[54] A. D'Alessio, M.S. Kluger, J.H. Li, R. Al-Lamki, J.R. Bradley, J.S. Pober, Targeting of tumor necrosis factor receptor 1 to low density plasma membrane domains in human endothelial cells, J. Biol. Chem. 285 (2010) 23868-23879.

[55] J.R. Bradley, D.R. Johnson, J.S. Pober, Four different classes of inhibitors of receptor-mediated endocytosis decrease tumor necrosis factor-induced gene expression in human endothelial cells, J. Immunol. 150 (1993) 5544-5555.

[56] W. Schneider-Brachert, V. Tchikov, J. Neumeyer, M. Jakob, S. Winoto-Morbach, J. Held-Feindt, et al., Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles, Immunity 21 (2004) 415-428.

[57] H. Choi, H.N. Nguyen, F.S. Lamb, lnhibition of endocytosis exacerbates TNF-alpha-induced endothelial dysfunction via enhanced JNK and p38 activation, Am. J. Physiol. Heart Circ. Physiol. 306 (2014) H1154-H1163.

[58] S. Schutze, V. Tchikov, W. Schneider-Brachert, Regulation of TNFR1 and CD95 signalling by receptor compartmentalization, Nat. Rev. Mol. Cell Biol. 9 (2008) 655-662.

[59] J. Neumeyer, C. Hallas, O. Merkel, S. Winoto-Morbach, M.Jakob, L. Thon, et al., TNF-receptor l defective in internalization allows for cell death through activation of neutral sphingomyelinase, Exp. Cell Res. 312 (2006) 2142-2153.

[60] B. Edelmann, U. Bertsch, V. Tchikov, S. Winoto-Morbach, C. Perrotta, M. Jakob, et al., Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase inTNF-R1 receptosomes, EMBOJ. 30 (2011) 379-394.

[61] A. Hupalowska, M. Miaczynska, The new faces of endocytosis in signaling, Traffic 13 (2012) 9-18.

[62] S. Sun, X. Zhou, W. Zhang, G.E. Gallick, J. Kuang, Unravelling the pivotal role of Alix in MVB sorting and silencing of the activated EGFR, Biochem. J. 466 (2015) 475-487.

[63] S. Sun, X. Zhou, J. Corvera, G.E. Gallick, S.-H. Lin, J. Kuang, ALG-2 activates the MVB sorting function of ALlX through relieving its intramolecular interaction, Cell Discov. 1 (2015) 15018.

[64] C. Bissig, J. Gruenberg, ALlX and the multivesicular endosome: ALlX in Wonderland, Trends Cell Biol. 24 (2014) 19-25.

[65] T. Falguieres, P.P. Luyet, C. Bissig, C.C. Scott, M.C. Velluz, J. Gruenberg, In vitro budding of intralumenal vesicles into late endosomes is regulated by Alix and Tsg101, Mol. Biol. Cell 19 (2008) 4942-4955.

[66] A.L. Mahul-Mellier, F. Strappazzon, A. Petiot, C. Chatellard-Causse, S. Torch, B. Blot, et al., Alix and ALG-2 are involved in tumor necrosis factor receptor 1-induced cell death, J. Biol. Chem. 283 (2008) 34954-34965.

[67] A. Algeciras-Schimnich, L. Shen, B.C. Barnhart, A.E. Murmann, J.K. Burkhardt, M.E. Peter, Molecular ordering of the initial signaling events of CD95, Mol. Cell. Biol. 22 (2002) 207-220.

[68] K.H. Lee, C. Feig, V. Tchikov, R. Schickel, C. Hallas, S. Schutze, et al., The role of receptor internalization in CD95 signaling, EMBOJ. 25 (2006) 1009-1023.

[69] C. Gajate, F. Mollinedo, Lipid rafts and raft-mediated supramolecular entities in the regulation of CD95 death receptor apoptotic signaling, Apoptosis 20 (2015) 584-606.

[70] K. Chakrabandhu, Z. Herincs, S. Huault, B. Dost, L. Peng, F. Conchonaud, et al., Palmitoylation is required for efficient Fas cell death signaling, EMBO J. 26 (2007) 209-220.

[71] C. Feig, V. Tchikov, S. Schutze, M.E. Peter, Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling, EMBOJ. 26 (2007) 221-231.

[72] S. Parlato, A.M. Giammarioli, M. Logozzi, F. Lozupone, P. Matarrese, F. Luciani, et al., CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway, EMBO J. 19 (2000) 5123-5134.

[73] K. Chakrabandhu, S. Huault, N. Garmy, J. Fantini, E. Stebe, S. Mailfert, et al., The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand, Cell Death Differ. 15 (2008) 1824-1837.

[74] A. Rossin, R. Kral, N. Lounnas, K. Chakrabandhu, S. Mailfert, D. Marguet, et al., Identification of a lysine-rich region of Fas as a raft nanodomain targeting signal necessary for Fas-mediated cell death, Exp. Cell Res. 316 (2010) 1513-1522.

[75] E. lessi, L. Zischler, A. Etringer, M. Bergeret, A. Morle, G. Jacquemin, et al., Death receptor-lnduced apoptosis signalling regulation by ezrin is cell type dependent and occurs in a DlSC-lndependent manner in colon cancer cells, PLoS One 10 (2015) e0126526.

[76] C.D. Austin, D.A. Lawrence, A.A. Peden, E.E. Varfolomeev, K. Totpal, A.M. De Maziere, et al., Death-receptor activation halts clathrin-dependent endocytosis, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 10283-10288.


J. Cendrowski et al./Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx

[79 [80

[82 [83 [84

[89 [90

[91 [92

[96 [97

S.L. Kohlhaas, A. Craxton, X.M. Sun, M.J. Pinkoski, G.M. Cohen, Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAlL)-induced apoptosis, J. Biol. Chem. 282 (2007)12831-1284 .

Y. Akazawa, J.L. Mott, S.F. Bronk, N.W. Werneburg, A. Kahraman, M.E. Guicciardi, et al., Death receptor 5 internalization is required for lysosomal permeabilization by TRAIL in malignant liver cell lines, Gastroenterology 136 (2009) 2365-2376 e1-e7.

M.S. Hayden, S. Ghosh, Regulation of NF-kappaB by TNF family cytokines, Semin. Immunol. 26 (2014) 253-266.

C. Remouchamps, L. Boutaffala, C. Ganeff, E. Dejardin, Biology and signal transduction pathways of the Lymphotoxin-alphabeta/LTbetaR system, Cytokine Growth Factor Rev. 22 (2011) 301-310.

T.L. VanArsdale, S.L. VanArsdale, W.R. Force, B.N. Walter, G. Mosialos, E. Kieff, et al., Lymphotoxin-beta receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappaB, Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 2460-2465. H. Nakano, H. Oshima, W. Chung, L. Williams-Abbott, C.F. Ware, H. Yagita, et al., TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor, J. Biol. Chem. 271 (1996) 14661-14664. Y.S. Kim, S.A. Nedospasov, Z.G. Liu, TRAF2 plays a key, nonredundant role in LlGHT-lymphotoxin beta receptor signaling, Mol. Cell. Biol. 25 (2005) 2130-2137.

C. Ganeff, C. Remouchamps, L. Boutaffala, C. Benezech, G. Galopin, S. Vandepaer, et al., lnduction of the alternative NF-kappaB pathway by lymphotoxin alphabeta (LTalphabeta) relies on internalization of LTbeta receptor, Mol. Cell. Biol. 31 (2011) 4319-4334.

A. Maminska, A. Bartosik, M. Banach-Orlowska, l. Pilecka, K. Jastrzebski, D. Zdzalik-Bielecka, et al., ESCRT proteins restrict constitutive NF-kappaB signaling by trafficking cytokine receptors, Sci. Signal. 9 (2016) ra8.

B. Zarnegar, J.Q. He, G. Oganesyan, A. Hoffmann, D. Baltimore, G. Cheng, Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 8108-8113.

R. Elgueta, M.J. Benson, V.C. de Vries, A. Wasiuk, Y. Guo, R.J. Noelle, Molecular mechanism and function of CD40/CD40L engagement in the immune system, lmmunol. Rev. 229 (2009) 152-172.

M. Xia, Q. Wang, H. Zhu, J. Ma, M. Hou, Z. Tang, et al., Lipid rafts regulate cellular CD40 receptor localization in vascular endothelial cells, Biochem. Biophys. Res. Commun. 361 (2007) 768-774.

H. Grassme, V. Jendrossek, J. Bock, A. Riehle, E. Gulbins, Ceramide-rich membrane rafts mediate CD40 clustering, J. Immunol. 168 (2002) 298-307. P.O. Vidalain, O. Azocar, C. Servet-Delprat, C. Rabourdin-Combe, D. Gerlier, S. Manie, CD40 signaling in human dendritic cells is initiated within membrane rafts, EMBO J. 19 (2000) 3304-3313.

H. Grassme, J. Bock, J. Kun, E. Gulbins, Clustering of CD40 ligand is required to form a functional contact with CD40, J. Biol. Chem. 277 (2002) 30289-30299.

B.S. Hostager, l.M. Catlett, G.A. Bishop, Recruitment of CD40 and tumor necrosis factor receptor-associated factors 2 and 3 to membrane microdomains during CD40 signaling, J. Biol. Chem. 275 (2000) 1539215398.

A. Nadiri, M.J. Polyak, M. Jundi, H. Alturaihi, C. Reyes-Moreno, G.S. Hassan, et al., CD40 translocation to lipid rafts: signaling requirements and downstream biological events, Eur. J. Immunol. 41 (2011) 2358-2367.

J. Chen, L. Chen, G. Wang, H. Tang, Cholesterol-dependent and -independent CD40 internalization and signaling activation in cardiovascular endothelial cells, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 2005-2013. Y. Chen, J. Chen, Y. Xiong, Q. Da, Y. Xu, X. Jiang, et al., Internalization of CD40 regulates its signal transduction in vascular endothelial cells, Biochem. Biophys. Res. Commun. 345 (2006) 106-117.

C. Garlanda, C.A. Dinarello, A. Mantovani, The interleukin-1 family: back to the future, Immunity 39 (2013) 1003-1018.

S.B. Mizel, P.L. Kilian, J.C. Lewis, K.A. Paganelli, R.A. Chizzonite, The interleukin 1 receptor. Dynamics of interleukin 1 binding and internalization in T cells and fibroblasts, J. Immunol. 138 (1987) 2906-2912.

B. Brissoni, L. Agostini, M. Kropf, F. Martinon, V. Swoboda, S. Lippens, et al., lntracellular trafficking of interleukin-1 receptor l requires Tollip, Curr. Biol. 16 (2006) 2265-2270.

A.M. Blanco, A. Perez-Arago, S. Fernandez-Lizarbe, C. Guerri, Ethanol mimics ligand-mediated activation and endocytosis of 1L-1R1/TLR4 receptors via lipid rafts caveolae in astroglial cells, J. Neurochem. 106 (2008) 625-639.

B. Hansen, O. Dittrich-Breiholz, M. Kracht, M. Windheim, Regulation of NF-kappaB-dependent gene expression by ligand-induced endocytosis of the interleukin-1 receptor, Cell. Signal. 25 (2013) 214-228.

M. Windheim, B. Hansen, lnterleukin-1-induced activation of the small GTPase Rac1 depends on receptor internalization and regulates gene expression, Cell. Signal. 26 (2014) 49-55.

Q. Li, M.M. Harraz, W. Zhou, L.N. Zhang, W. Ding, Y. Zhang, et al., Nox2 and Rac1 regulate H2O2-dependent recruitment of TRAF6 to endosomal interleukin-1 receptor complexes, Mol. Cell. Biol. 26 (2006) 140-154. B.M. Curtis, M.B. Widmer, P. deRoos, E.E. Qwarnstrom, lL-1 and its receptor are translocated to the nucleus, J. Immunol. 144 (1990) 1295-1303. M.N. Weitzmann, N. Savage, Nuclear internalisation and DNA binding activities of interleukin-1, interleukin-1 receptor and interleukin-1/receptor complexes, Biochem. Biophys. Res. Commun. 187 (1992) 1166-1171.

G. Bol, O.J. Kreuzer, R. Brigelius-Flohe, Translocation of the interleukin-1 receptor-associated kinase-1 (1RAK-1) into the nucleus, FEBS Lett. 477 (2000) 73-78.

A. Bavelloni, S. Santi, A. Sirri, M. Riccio, 1. Faenza, N. Zini, et al., Phosphatidylinositol 3-kinase translocation to the nucleus is induced by interleukin 1 and prevented by mutation of interleukin 1 receptor in human osteosarcoma Saos-2 cells, J. Cell Sci. 112 (Pt. 5) (1999) 631-640. M.S. Gresnigt, F.L. van de Veerdonk, Biology of 1L-36 cytokines and their role in disease, Semin. 1mmunol. 25 (2013) 458-465.

S.S. Saha, D. Singh, E.L. Raymond, R. Ganesan, G. Caviness, C. Grimaldi, et al., Signal transduction and intracellular trafficking by the interleukin 36 receptor, J. Biol. Chem. 290 (2015) 23997-24006.

T.A. Waldmann, The shared and contrasting roles of 1L2 and 1L15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy, Cancer 1mmunol. Res. 3 (2015) 219-227.

Y. Rochman, R. Spolski, W.J. Leonard, New insights into the regulation of T cells by gamma(c) family cytokines, Nat. Rev. 1mmunol. 9 (2009) 480-490. R. Meazza, B. Azzarone, A.M. Orengo, S. Ferrini, Role of common-gamma chain cytokines in NK cell development and function: perspectives for immunotherapy, J. Biomed. Biotechnol. 2011 (2011) 861920. E. Morelon, A. Dautry-Varsat, Endocytosis of the common cytokine receptor gammac chain: identification of sequences involved in internalization and degradation, J. Biol. Chem. 273 (1998) 22044-22051. N. Sauvonnet, A. Dujeancourt, A. Dautry-Varsat, Cortactin and dynamin are required for the clathrin-independent endocytosis of gammac cytokine receptor, J. Cell Biol. 168 (2005) 155-163.

V. Duprez, A. Dautry-Varsat, Receptor-mediated endocytosis of interleukin 2 in a human tumor T cell line. Degradation of interleukin 2 and evidence for the absence of recycling of interleukin receptors, J. Biol. Chem. 261 (1986) 15450-15454.

V. Duprez, V. Cornet, A. Dautry-Varsat, Down-regulation of high affinity interleukin 2 receptors in a human tumor T cell line. 1nterleukin 2 increases the rate of surface receptor decay, J. Biol. Chem. 263 (1988) 12860-12865. A. Yu, F. Olosz, C.Y. Choi, T.R. Malek, Efficient internalization of 1L-2 depends on the distal portion of the cytoplasmic tail of the 1L-2R common gamma-chain and a lymphoid cell environment, J. 1mmunol. 165 (2000) 2556-2562. A. Hemar, A. Subtil, M. Lieb, E. Morelon, R. Hellio, A. Dautry-Varsat, Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor alpha, beta, and gamma chains, J. Cell Biol. 129 (1995) 55-64.

A. Subtil, A. Hemar, A. Dautry-Varsat, Rapid endocytosis of interleukin 2 receptors when clathrin-coated pit endocytosis is inhibited, J. Cell Sci. 107 (Pt. 12) (1994) 3461-3468.

C. Basquin, N. Sauvonnet, Phosphoinositide 3-kinase at the crossroad between endocytosis and signaling of cytokine receptors, Commun. 1ntegr. Biol. 6 (2013) e24243.

C. Basquin, V. Malarde, P. Mellor, D.H. Anderson, V. Meas-Yedid, J.C. Olivo-Marin, et al., The signalling factor P13K is a specific regulator of the clathrin-independent dynamin-dependent endocytosis of 1L-2 receptors, J. Cell Sci. 126 (2013) 1099-1108.

A. Grassart, A. Dujeancourt, P.B. Lazarow, A. Dautry-Varsat, N. Sauvonnet, Clathrin-independent endocytosis used by the 1L-2 receptor is regulated by Rac1, Pak1 and Pak2, EMBO Rep. 9 (2008) 356-362. C. Basquin, M. Trichet, H. Vihinen, V. Malarde, T. Lagache, L. Ripoll, et al., Membrane protrusion powers clathrin-independent endocytosis of interleukin-2 receptor, EMBO J. 34 (2015) 2147-2161.

H. Gandhi, R. Worch, K. Kurgonaite, M. Hintersteiner, P. Schwille, C. Bokel, et al., Dynamics and interaction of interleukin-4 receptor subunits in living cells, Biophys. J. 107 (2014) 2515-2527.

K. Kurgonaite, H. Gandhi, T. Kurth, S. Pautot, P. Schwille, T. Weidemann, et al., Essential role of endocytosis for interleukin-4-receptor-mediated JAK/STAT signalling, J. Cell Sci. 128 (2015) 3781-3795.

N. Geijsen, L. Koenderman, P.J. Coffer, Specificity in cytokine signal transduction: lessons learned from the 1L-3/1L-5/GM-CSF receptor family, Cytokine Growth Factor Rev. 12 (2001) 19-25.

R.P. de Groot, P.J. Coffer, L. Koenderman, Regulation of proliferation, differentiation and survival by the 1L-3/1L-5/GM-CSF receptor family, Cell. Signal. 10 (1998) 619-628.

N. Sato, C. Caux, T. Kitamura, Y. Watanabe, K. Arai, J. Banchereau, et al., Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells, Blood 82 (1993) 752-761. M. Martinez-Moczygemba, D.P. Huston, J.T. Lei, JAK kinases control 1L-5 receptor ubiquitination, degradation, and internalization, J. Leukoc. Biol. 81 (2007) 1137-1148.

J.T. Lei, M. Martinez-Moczygemba, Separate endocytic pathways regulate 1L-5 receptor internalization and signaling, J. Leukoc. Biol. 84 (2008) 499-509. J.T. Lei, T. Mazumdar, M. Martinez-Moczygemba, Three lysine residues in the common beta chain of the interleukin-5 receptor are required for Janus kinase (JAK)-dependent receptor ubiquitination, endocytosis, and signaling, J. Biol. Chem. 286 (2011) 40091-40103.

M. Martinez-Moczygemba, D.P. Huston, Proteasomal regulation of betac signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization, J. Clin. 1nvestig. 108 (2001) 1797-1806. X. Wang, P. Lupardus, S.L. Laporte, K.C. Garcia, Structural biology of shared cytokine receptors, Annu. Rev. 1mmunol. 27 (2009) 29-60.


J. Cendrowski et al./Cytokine & Growth Factor Reviews xxx (2016) xxx-xxx

[133 [134

[135 [136 [137 [138 [139 [140

[142 [143

[145 [146 [147

[150 [151

J. Wolf, S. Rose-John, C. Garbers, Interleukin-6 and its receptors: a highly regulated and dynamic system, Cytokine 70 (2014) 11 -20. H. Kim, H. Baumann, Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells, Mol. Cell. Biol. 19 (1999) 5326-5338.

V. Giordano, G. De Falco, R. Chiari, I. Quinto, P.G. Pelicci, L. Bartholomew, et al., Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase, J. Immunol. 158 (1997) 4097-4103.

P.C. Heinrich, I. Behrmann, G. Muller-Newen, F. Schaper, L. Graeve, Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway, Biochem. J. 334 (Pt. 2) (1998) 297-314.

S. Thiel, H. Dahmen, A. Martens, G. Muller-Newen, F. Schaper, P.C. Heinrich, et al., Constitutive internalization and association with adaptor protein-2 of the interleukin-6 signal transducer gp130, FEBS Lett. 441 (1998) 231-234. S. Thiel, I. Behrmann, E. Dittrich, L. Muys, J. Tavernier, J. Wijdenes, et al., Internalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway, Biochem. J. 330 (Pt. 1) (1998) 47-54. Y. Tanaka, N. Tanaka, Y. Saeki, K. Tanaka, M. Murakami, T. Hirano, et al., c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130, Mol. Cell. Biol. 28 (2008) 4805-4818.

E. Dittrich, C.R. Haft, L. Muys, P.C. Heinrich, L. Graeve, A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor, J. Biol. Chem. 271 (1996) 5487-5494.

Y. Koshelnick, M. Ehart, P. Hufnagl, P.C. Heinrich, B.R. Binder, Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598, J. Biol. Chem. 272 (1997) 28563-2856 .

P.B. Sehgal, G.G. Guo, M. Shah, V. Kumar, K. Patel, Cytokine signaling: STATS in plasma membrane rafts, J. Biol. Chem. 277 (2002) 12067-12074. T. Yamaguchi, K. Naruishi, H. Arai, F. Nishimura, S. Takashiba, IL-6/sIL-6R enhances cathepsin B and L production via caveolin-1-mediated JNK-AP-1 pathway in human gingival fibroblasts, J. Cell. Physiol. 217 (2008) 423-432. C.L. German, B.M. Sauer, C.L. Howe, The STAT3 beacon: IL-6 recurrently activates STAT 3 from endosomal structures, Exp. Cell Res. 317 (2011) 1955-1969.

S. Parmar, L.C. Platanias, Interferons: mechanisms of action and clinical applications, Curr. Opin. Oncol. 15 (2003) 431-439.

G.R. Stark, I.M. Kerr, B.R. Williams, R.H. Silverman, R.D. Schreiber, How cells respond to interferons, Annu. Rev. Biochem. 67 (1998) 227-264.

S. Pestka, S.V. Kotenko, G. Muthukumaran, L.S. Izotova, J.R. Cook, G. Garotta, The interferon gamma (IFN-gamma) receptor: a paradigm for the multichain cytokine receptor, Cytokine Growth Factor Rev. 8 (1997) 189-206. A. Takaoka, Y. Mitani, H. Suemori, M. Sato, T. Yokochi, S. Noguchi, et al., Cross talk between interferon-gamma and -alpha/beta signaling components in caveolar membrane domains, Science 288 (2000) 2357-2360. M. Marchetti, M.N. Monier, A. Fradagrada, K. Mitchell, F. Baychelier, P. Eid, et al., Stat-mediated signaling induced by type I and type II interferons (IFNs) is differentially controlled through lipid microdomain association and clathrin-dependent endocytosis of IFN receptors, Mol. Biol. Cell 17 (2006) 2896-2909.

P.S. Subramaniam, H.M. Johnson, Lipid microdomains are required sites for the selective endocytosis and nuclear translocation of IFN-gamma, its receptor chain IFN-gamma receptor-1, and the phosphorylation and nuclear translocation of STAT1alpha, J. Immunol. 169 (2002) 1959-1969.

H. Zheng, J. Qian, D.P. Baker, S.Y. Fuchs, Tyrosine phosphorylation of protein kinase D2 mediates ligand-inducible elimination of the Type 1 interferon receptor, J. Biol. Chem. 286 (2011) 35733-3574 .

[152] K.G. Kumar, H. Barriere, C.J. Carbone, J. Liu, G. Swaminathan, P. Xu, et al., Site-specific ubiquitination exposes a linear motif to promote interferon-alpha receptor endocytosis, J. Cell Biol. 179 (2007) 935-950.

[153] C.M. Ahmed, M.A. Burkhart, M.G. Mujtaba, P.S. Subramaniam, H.M.Johnson, The role of IFNgamma nuclear localization sequence in intracellular function, J. Cell Sci. 116 (2003) 3089-3098.

Jaroslaw Cendrowski received his PhD in Biochemistry, Molecular Biology and Biomedicine from Autonomous University of Madrid in 2013. He carried out the PhD project at the Spanish National Cancer Research Centre (CNIO) in Madrid, Spain under the supervision of Francisco X. Real. Currently, he works as a postdoctoral fellow at the International Institute of Molecular and Cell Biology in Warsaw in the laboratory of Marta Miaczynska. His research interests include the role of endocytosis in regulation of intracellular signaling in the context of inflammation, cancer and development.

Agnieszka Maminska obtained her PhD in Cell Biology with distinction in 2015, after performing the doctoral project in the International Institute of Molecular and Cell Biology in Warsaw in the laboratory of Marta Miaczynska. She is currently a postdoctoral fellow in the same group. She carried out laboratory trainings at the University of Glasgow (UK), University of Chicago (USA) and University of Oslo (Norway). Her scientific interests include interplay of endocytosis with signal transduction, mechanisms of receptor trafficking in the cell and role of membrane transport in host-pathogen interactions.

Marta Miaczynska is head of the Laboratory of Cell Biology at the International Institute of Molecular and Cell Biology in Warsaw since 2005 and a full professor since 2013. She received her PhD in genetics in 1997 from Vienna University and did postdoctoral work at the European Molecular Biology Laboratory in Heidelberg and at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden. She has received numerous fellowships and grants, such as Human Frontier Science Program Organization fellowship, Wellcome Trust Senior Research Fellowship (UK), International Scholar of the Howard Hughes Medical Institute (USA), L'Oreal Poland fellowship for Women in Science, MAESTRO grant from the National Science Center or a grant from the Polish-Swiss Research Programme. Her research interests have focused on the molecular mechanisms integrating membrane transport with signal transduction in the cell, in particular the biogenesis of endosomes and their functions in signaling.