Physiological Laboratory, University of Liverpool, Crown St., Liverpool L69 3BX, UK
*Author for correspondence (e-mail: clague{at}liv.ac.uk)
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SUMMARY |
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Key words: Endocytosis, Tyrosine kinase receptor, Rab5, Hrs, Hgs, EGF receptor, Cbl
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Introduction |
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Recent work has revealed more subtle regulation of receptor signalling as a function of receptor dynamics. Subcellular localisation can determine the identity of effector molecules that couple to activated receptors and thus the relative strengths of different signalling pathways.
EGFR typically recycles through the sorting or early endosome to the plasma membrane an estimated 3-5 times before it is selected for degradation in a stochastic manner by routing to late endosomal compartments. At steady state, 70-80% of the EGF-occupied receptor is endosomal (Sorkin, 1998). Several lines of evidence suggest that the receptor can maintain its activated state during a substantial part of this cycle. The ability of the receptor to autophosphorylate is maintained (Lai et al., 1989), and various signalling molecules, such as Shc, Grb2 and mSOS, redistribute to early endosomes in a ligand-dependent manner (Di Guglielmo et al., 1994; Oskvold et al., 2000). One is led to the conclusion that the majority of EGF-dependent receptor signalling actually occurs from endosomal compartments. Even after normalisation for receptor density, the specific activity of some receptor signalling events will be enriched on endosomes simply by a temporal coincidence the rate at which signals pass down a pathway versus the receptor internalisation rate. But can location actually determine or specify signalling outcomes? Very probably. Vieira et al. have examined the influence of endocytic trafficking on EGF-dependent signalling after imposing a block on EGFR endocytosis by expression of a dominant negative form of dynamin (Vieria et al., 1996). They found that the mutant dynamin changed the relative strength of EGF-dependent signalling pathways; for example, Erk1 phosphorylation dramatically decreased whereas phospholipase C phosphorylation increased.
If membrane trafficking can influence signal transduction, then it should be no surprise if the reverse is true nature loves a feedback loop after all. For coupling to occur, a factor must engage with both processes. Here, we highlight three examples of proteins that can regulate aspects of both EGFR trafficking and signalling.
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Rab5 |
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It has long been known that EGF stimulates not only receptor downregulation but also fluid-phase internalisation. Barbieri et al. have recently shown that both forms of stimulated endocytosis are Rab5 dependent and coupled to Rab5 activation (Barbieri et al., 2000). Addition of EGF to serum-starved cells leads to GTP loading of Rab5. This pathway might involve PI 3-kinase and protein kinase B (PKB/Akt), because wortmannin and expression of dominant negative PKB/Akt block the stimulation of endocytosis by EGF (Barbieri et al., 2000). Interestingly, Christoforidis et al. have shown that Rab5 interacts with two PI 3-kinases, hVPS34 and p110ß, using affinity chromatography with a Rab5-GTP column (Christoforidis et al., 1999). The hVPS34 enzyme (a class III PI 3-kinase, the human homologue of Vps34p the only PI 3-kinase in yeast) generates phosphatidylinositol 3-phosphate (PtdIns(3)P), which in turn cooperates with Rab5 itself to recruit EEA1 to endosomes, where it is believed to participate in endosome fusion events (Mills et al., 1998; Simonsen et al., 1998). The interaction between Rab5 and p110ß PI 3-kinase (a class I PI 3-kinase) suggests that Rab5 may play a role in the localised production of PtdIns(3,4)P2 and PtdIns(3,4,5)P3 and consequent activity of downstream effectors (e.g. PKB). Among other outputs, this may provide a positive feedback loop by stimulating further activation of Rab5 (Barbieri et al., 1998).
Lanzetti et al. have recently uncovered a mechanism that might limit the stimulatory effects of EGF described above. Eps8 is a substrate for the EGF receptor kinase and can recruit RN-tre (related to the N-terminus of TRE; (Matoskova et al., 1996b) to the plasma membrane through its SH3 domain (Matoskova et al., 1996a). Lanzetti et al. have shown that RN-tre can act as a Rab5 GAP and thereby inactivate Rab5 by stimulating its GTP hydrolysis. Indeed over-expression of RN-tre leads to reduction of both EGF and transferrin endocytosis, except in Eps8-null fibroblasts, in which only transferrin uptake is inhibited (Lanzetti et al., 2000). A further consequence of RN-tre expression is inhibition of Eps8-dependent Rac activation: RN-tre competes for Eps8 binding with E3bl, an adapter protein that recruits Sos-1, an exchange factor for Rac (Scita et al., 1999). Thus, inhibition of EGFR endocytosis and Rac signalling are coupled through Eps8-dependent recruitment of RN-tre (Lanzetti et al., 2000).
A key component of the Rab5 cycle is Rab-GDI, which sequesters multiple Rab proteins away from membranes in their GDP-bound form and chaperones them within the cytosol (Ullrich et al., 1993). The observation that GDI is phosphorylated led to the suggestion that this provides a signal for coordinated regulation of Rab family activity (Steele-Mortimer et al., 1993). Cavalli et al. have recently identified a GDI-activating factor as p38 MAP kinase, which phosphorylates GDI and thereby causes extraction of Rab5 from membranes (Cavalli et al., 2001). These authors linked the p38-induced stress response following peroxide treatment or UV illumination to an increase in the endocytic rate constant that correlates with p38-dependent promotion of cytosolic GDI-Rab5 complex formation. At first this result seems counterintuitive, because Rab5 is active at membranes, but the authors argue that it reflects the increased turnover of Rab5, which is known to be linked to nucleotide exchange. Note that in BHK cells up to 80% of membrane-bound Rab5 is in the inactive GDP-bound form (Stenmark et al., 1994). Cytosolic Rab5-GDI may therefore be limiting in endocytic transport, as has been suggested by studies of clathrin-coated vesicle formation in a permeabilised cell assay (McLauchlan et al., 1998). These studies have revealed a hitherto unsuspected aspect of the stress-response programme: an acceleration of endocytic rate that is likely to be mediated by p38-dependent phosphorylation of GDI (Cavalli et al., 2001).
The recent data described above point to a central role for the endocytosis regulator Rab5 in coordinating the response to various stimuli. Three aspects of the Rab5 cycle GTP exchange, GTP hydrolysis and GDI sequestration thus intersect with classical cell signalling pathways (Fig. 1). Rab 5 may translate these signals by influencing receptor localisation and hence signalling output as discussed above, but may also directly influence signalling by recruitment of effector proteins (e.g. PI 3-kinase enzymes) to endosomes.
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Hrs |
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Internalisation of EGFR to Hrs-containing endosomes is required for EGF-induced Hrs phosphorylation (Urbé et al., 2000). This phosphorylation event requires PI 3-kinase activity, as evidenced by its sensitivity to wortmannin. This is at least in part due to interaction of PtdIns(3)P with the FYVE domain, which contributes to the localisation of Hrs on endosomes. Interestingly, once phosphorylated, Hrs seems to be released from the endosome membrane to the cytosolic pool (Urbé et al., 2000).
Two proteins that bind to Hrs have been identified: signal-transducing adapter molecule (STAM) and Hrs-binding protein (Hbp), the mouse homologue of human STAM-2 (Asao et al., 1997; Endo et al., 2000; Takata et al., 2000). Human STAM and STAM-2 share 57% sequence identity, each bears an SH3 domain and both are also tyrosine phosphorylated. In T cells, overexpression of Hrs leads to suppression of cytokine-mediated DNA synthesis, whereas overexpression of a mutant unable to bind STAM has no effect (Asao et al., 1997). A highly related chicken protein, EAST (EGF-receptor-associated protein with SH3 and TAM domains), which associates with EGFR and Eps15, is also phosphorylated after EGF stimulation (Lohi et al., 1998). Saccharomyces cerevisiae contains a single Hbp/STAM homologue, YHL002W, which has been shown to interact with the Hrs homologue Vps27p in a systematic two-hybrid screen (Uetz et al., 2000).
NIH3T3 cells stably transfected with Hbp mutants that lack the SH3 domain or the binding site for Hrs exhibit impaired degradation of internalised PDGF (Takata et al., 2000). This latter result is consistent with a role for the Hrs-Hbp complex in regulating transport from early to late endosomes (or multi-vesicular bodies) proposed by analogy with Vps27p function in yeast.
A two-hybrid screen revealed a further interesting partner for Hrs, the rat homologue of human sorting nexin 1 (SNX1) (Chin et al., 2001), which shares with Hrs the ability to bind to PtdIns3P, (although SNX1 utilises a PX domain rather than a FYVE domain) (Wishart et al., 2001). SNX1 also interacts directly with the lysosomal sorting signal of EGFR, and its overexpression leads to increased receptor degradation (Kurten et al., 1996). There is an overlap between the EGFR- and Hrs-binding sites of SNX1, and the interactions appear to be mutually exclusive (Chin et al., 2001). This suggests Hrs might act as a negative regulator of EGFR degradation by sequestering SNX1 at the membrane. The observation that overexpression of Hrs, or more crucially the SNX1-binding domain of Hrs, inhibits EGFR degradation in HeLa cells supports such a model (Chin et al., 2001). The Hrs-SNX1 complex is found only in particulate fractions, whereas each protein exists in a separate cytosolic pool. Perhaps phosphorylation of Hrs, which we have proposed leads to its release from the membrane (Urbé et al., 2000), provides the trigger for the dissociation of the Hrs-SNX1 complex. This model is attractive because it provides a mechanism for the receptor to govern its own fate at the endosome by coupling the receptor-mediated phosphorylation of Hrs-Hbp to availability of a sorting factor (Fig. 2).
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Hrs function is thus clearly multifaceted. By virtue of multiple interactions that are depicted in Fig. 2, it is able both to regulate receptor trafficking and to participate in signal transduction pathways.
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Cbl |
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Phosphorylation of Y1045 of the EGFR is required for Cbl recruitment, and its mutation blocks receptor ubiquitination and downregulation (Levkowitz et al., 1999). However, a recent paper has challenged a causative relationship between receptor ubiquitination and Cbl-dependent downregulation (Thien et al., 2001) (see Fig. 3). A Y368F-Cbl linker region mutant is as effective as wild-type Cbl in promoting EGFR ubiquitination but does not have an equivalent ability to inhibit receptor recycling when expressed in NIH3T3 cells. Conversely, a Y371F-Cbl mutant is unable to promote receptor polyubiquitination and yet resembles wild-type Cbl in its inhibition of receptor recycling (Thien et al., 2001). One must therefore consider the possibility that targets for ubiquitination other than the receptor itself have an influence on receptor sorting. Alternatively, Cbl might act through a ubiquitin-independent mechanism to promote receptor degradation. A caveat to this challenging study is that the measured amount of recycling receptor was small in the control cells (NIH3T3 cells expressing relatively low amounts of receptor) (Thien et al., 2001).
There are many other aspects to Cbl function beyond its role as an E3 ligase (reviewed by Thien and Langdon, 2001). Disruptions of the RING-finger domain abolish this activity but are insufficient to convert Cbl to an oncogenic protein (Thien et al., 2001). The critical region for oncogenesis appears to be an -helical linker domain that connects the RING finger to the SH2 region of the TKB domain (Thien et al., 2001). The RING-finger domain of Cbl can also interact with Sprouty, an antagonist of tyrosine kinase receptor signalling (Wong et al., 2001). Cbl itself is a substrate for tyrosine kinases and may function as an adapter protein. Phosphorylation of Y700 and Y774 provides a docking site for the adapter protein CrkL, which can lead to JNK activation downstream of Met receptor stimulation (Garcia-Guzman et al., 2000). Phosphorylated Y731 provides a docking site for the p85 PI 3-kinase adapter subunit (Hartley and Corvera, 1996). Furthermore, Cbl apparently exerts a positive regulatory role in integrin signaling downstream of Src by recruiting both PI 3-kinase and CrkL (Feshchenko et al., 1999).
The details of the influence of Cbl on cellular signalling remain to be fully explored, but all the signs are that it can combine regulation of receptor trafficking and signalling, in part by functioning as an adapter protein.
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Conclusions |
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ACKNOWLEDGMENTS |
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