Role of Rab5 in EGF receptor-mediated signal transduction

Barbieri, M. Alejandro; Fernandez‐Pol, Sebastian; Hunker, C.M.; Horazdovsky, Bruce F.; Stahl, Philip D.

doi:10.1078/0171-9335-00381

Cited by 84 publications

(71 citation statements)

References 28 publications

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“…Two paradoxical findings changed the focus of our work. 1) When we overexpressed Rin1, we blocked EGF-triggered activation of the Raf kinase pathway and the proliferative response to EGF (36). 2) When we overexpressed Rab5a, we enhanced the signaltransducing properties of EGF including cell proliferation (36).…”

Section: Discussionmentioning

confidence: 99%

“…1) When we overexpressed Rin1, we blocked EGF-triggered activation of the Raf kinase pathway and the proliferative response to EGF (36). 2) When we overexpressed Rab5a, we enhanced the signaltransducing properties of EGF including cell proliferation (36). We queried how it could be that overexpression of Rin1, an activator of Rab5, suppressed EGFR signaling, whereas overexpression of Rab5, the target of the guanine nucleotide exchange factor activity of Rin1, enhanced EGFR signaling.…”

Section: Discussionmentioning

confidence: 99%

“…NR6-RGFR-Rin1 and NR6-EGFR-vector stable cell lines were described in Ref. 36. Cos7 or HeLa cells were transfected using FuGENE 6 (Roche Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

“…The Rin family now has at least four members, all of which have active Rab5 guanine nucleotide exchange factor domains (32)(33)(34)(35). Subsequent work showed that Rin1 is recruited to the EGFR via its SH2 domain and that it regulates EGF-induced signal transduction (36,37). Identification of additional Rin1-interacting partners is critical to understanding the dynamic of EGFR trafficking.…”

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confidence: 99%

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Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Chen

et al. 2007

Journal of Biological Chemistry

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Rin1, the prototype of a new family of multidomain Rab5 exchange factors, has been shown to play an important role in the endocytosis of the epidermal growth factor receptor (EGFR). Herein, we examined the role of Rin1 in the down-regulation of EGFR following EGF stimulation. We observed that overexpression of Rin1 accelerates EGFR degradation in EGF-stimulated cells. In concordance, depletion of endogenous Rin1 by RNA interference resulted in a substantial reduction of EGFR degradation. We showed that Rin1 interacts with signal-transducing adaptor molecule 2 (STAM2), a protein that associates with hepatocyte growth factor-regulated substrate and plays a key role in the endosomal sorting machinery. Green fluorescent protein (GFP)-Rin1 co-localizes with hemagglutinin (HA)-STAM2 and with endogenous hepatocyte growth factor-regulated substrate. Furthermore, wild type STAM2, but not a deletion mutant lacking the SH3 domain, co-immunoprecipitates with endogenous Rin1. This interaction is dependent on the proline-rich domain (PRD) of Rin1 as Rin1⌬PRD, a mutant lacking the PRD, does not interact with STAM2. Moreover, EGFR degradation was not accelerated by expression of the Rin1⌬PRD mutant. Together these results suggest that Rin1 regulates EGFR degradation in cooperation with STAM, defining a novel role for Rin1 in regulating endosomal trafficking. The epidermal growth factor receptor (EGFR)2 plays a central role in cell proliferation, differentiation, survival, and migration (1, 2) and has served as a prototype in growth factor receptor trafficking. Following activation, EGFR with intrinsic tyrosine kinase activity is rapidly internalized by clathrincoated pits (3), sorted through early endosomes, and eventually transported to and degraded within multivesicular bodies (MVB) and lysosomes (4, 5). The process is generally known as receptor down-regulation and is considered to be an important cellular strategy for signal attenuation (6, 7). Alterations in receptor trafficking and signal attenuation have been associated with carcinogenesis (5, 8) and certain developmental processes, which has stimulated interest in the molecular mechanisms that regulate EGFR trafficking and degradation.EGFR targeted for lysosomal degradation is delivered to the MVB by a highly specialized process that begins with receptor ubiquitination and sequestration by elements of the ESCRT (endosomal sorting complex required for transport) complex on the surface of the early endosomes (9, 10). Invagination of the endosomal membrane and delivery of sequestered receptors into the lumen of the MVB is accompanied by receptor deubiquitination and disassembly of the ESCRT complex (11,12). The ESCRT machinery, first identified in yeast as class E Vps (vacuolar protein sorting) mutants (13) and highly conserved among eukaryotic cells (14), is important in targeting EGFR into the lumen of the MVB (15, 16). Substantial progress has been made in identifying the molecular mechanisms involved (12,17). Among the early acting factors are Hrs (hepatocyte growth fa...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…NR6-RGFR-Rin1 and NR6-EGFR-vector stable cell lines were described in Ref. 36. Cos7 or HeLa cells were transfected using FuGENE 6 (Roche Diagnostics).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Chen

et al. 2007

Journal of Biological Chemistry

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“…Rab5 is involved in the transport of several receptors. The expression of constitutively active Rab5 (Q79L) causes ligand-independent EGFR internalization, while the expression of dominant negative Rab5 (S34N) blocks EGF-stimulated and receptor-mediated endocytosis, which affects EGF activation in the Raf-Erk kinase pathway [34][35][36]. Rab5 was also found to be involved in insulin receptor-mediated endocytosis [37].…”

Section: Discussionmentioning

confidence: 99%

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

2008

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In eukaryotic cells, receptor endocytosis is a key event regulating signaling transduction. Adiponectin receptors belong to a new receptor family that is distinct from G-protein-coupled receptors and has critical roles in the pathogenesis of diabetes and metabolic syndrome. Here, we analyzed the endocytosis of adiponectin and adiponectin receptor 1 (AdipoR1) and found that they are both internalized into transferrin-positive compartments that follow similar traffic routes. Blocking clathrin-mediated endocytosis by expressing Eps15 mutants or depleting K + trapped AdipoR1 at the plasma membrane, and K + depletion abolished adiponectin internalization, indicating that the endocytosis of AdipoR1 and adiponectin is clathrin-dependent. Depletion of K + and overexpression of Eps15 mutants enhance adiponectinstimulated AMP-activated protein kinase phosphorylation, suggesting that the endocytosis of AdipoR1 might downregulate adiponectin signaling. In addition, AdipoR1 colocalizes with the small GTPase Rab5, and a dominant negative Rab5 abrogates AdipoR1 endocytosis. These data indicate that AdipoR1 is internalized through a clathrin-and Rab5-dependent pathway and that endocytosis may play a role in the regulation of adiponectin signaling.

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Rab GTPases regulating receptor trafficking at the late endosome–lysosome membranes

Gan

et al. 2012

Cell Biochemistry & Function

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Lysosomes serve key degradative functions for the turnover of membrane lipids and protein components. Its biogenesis is principally dependent on exocytic traffic from the late endosome via the trans-Golgi network, and it also receives cargo to be degraded from the endocytic pathway. Membrane trafficking to the late endosome-lysosome is tightly regulated to maintain the amplitude of signalling events and cellular homeostasis. Key coordinators of lysosomal traffic include members of the Rab small GTPase family. Amongst these, Rab7, Rab9 and the more recently studied Rab22B/31 have all been reported to regulate membrane trafficking processed at the late endosome-lysosome system. We discuss what is known about the roles of these Rab proteins and their interacting partners on the regulation of traffic of important receptor proteins such as the epidermal growth factor receptor (EGFR) and the mannose 6-phosphate receptor (M6PR), in association with the late endosome-lysosome system. Better knowledge of EGFR and M6PR traffic in this regard may aid in understanding the pathological processes, such as oncogenic transformations associated with these receptors.

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Role of Rab5 in EGF receptor-mediated signal transduction

Cited by 84 publications

References 28 publications

Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation

Endocytosis of adiponectin receptor 1 through a clathrin- and Rab5-dependent pathway

Rab GTPases regulating receptor trafficking at the late endosome–lysosome membranes

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