TY - JOUR
T1 - Role of Rab5 in EGF receptor-mediated signal transduction
AU - Barbieri, M. Alejandro
AU - Fernandez-Pol, Sebastian
AU - Hunker, Christine
AU - Horazdovsky, Bruce H.
AU - Stahl, Philip D.
N1 - Funding Information:
Acknowledgements. We thank E. Peters for excellent technical assistance and D. Owyoung for editing assistance. This work was supported in part by grants from the National Institutes of Health (GM42259, AI35884, and AI20015 to P. D. Stahl), the Jose Carreras International Leukemia Foundation, the Siteman Cancer Center and the Diabetes Research and Training Center (E. D. Thomas Fellowship Program, IRG5801045 ± 1 and 2P60DK20579 to M. A. Barbieri) at Washington University School of Medicine.
PY - 2004/7
Y1 - 2004/7
N2 - Activated epidermal growth factor receptor (EGFR) recruits intracellular proteins that mediate receptor trafficking and signaling. Rab5 and Rin1, a multifunctional protein with a Rab5 guanine nucleotide exchange factor domain, have been shown to regulate EGFR endocytosis (Barbieri et al., 2000; Tall et al., 2001). In this study, we demonstrate that overexpression of both dominant negative Rab5 (Rab5:S34N) and full-length Rin1 selectively block EGF activation of the Raf-Erk1/2 kinase pathway and EGF-stimulated incorporation of [3H]thymidine into DNA without affecting the activity of JN and p38 kinase pathways. Expression of Rab5:S34N and Rin1 also block EGF induction of cyclin D1 transcription. In contrast, expression of Rin1:Δ, a natural splice variant of Rin1 lacking 47 amino acids in the Vps9p domain or Rab5, increase both activation of Raf-Erk1/2- and cyclin D1 transcription in response to EGF. These results indicate that Rab5 and the Raf/Erk signal transduction pathway play essential and selective roles in EGF-induced cell proliferation, and highlight a new function for Rab5 in EGF signaling.
AB - Activated epidermal growth factor receptor (EGFR) recruits intracellular proteins that mediate receptor trafficking and signaling. Rab5 and Rin1, a multifunctional protein with a Rab5 guanine nucleotide exchange factor domain, have been shown to regulate EGFR endocytosis (Barbieri et al., 2000; Tall et al., 2001). In this study, we demonstrate that overexpression of both dominant negative Rab5 (Rab5:S34N) and full-length Rin1 selectively block EGF activation of the Raf-Erk1/2 kinase pathway and EGF-stimulated incorporation of [3H]thymidine into DNA without affecting the activity of JN and p38 kinase pathways. Expression of Rab5:S34N and Rin1 also block EGF induction of cyclin D1 transcription. In contrast, expression of Rin1:Δ, a natural splice variant of Rin1 lacking 47 amino acids in the Vps9p domain or Rab5, increase both activation of Raf-Erk1/2- and cyclin D1 transcription in response to EGF. These results indicate that Rab5 and the Raf/Erk signal transduction pathway play essential and selective roles in EGF-induced cell proliferation, and highlight a new function for Rab5 in EGF signaling.
KW - EGF
KW - Rab5
KW - Rin1
KW - Signal transduction
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U2 - 10.1078/0171-9335-00381
DO - 10.1078/0171-9335-00381
M3 - Article
C2 - 15511088
AN - SCOPUS:4744360232
SN - 0171-9335
VL - 83
SP - 305
EP - 314
JO - European Journal of Cell Biology
JF - European Journal of Cell Biology
IS - 6
ER -