Role of rab5 in EGF receptor-mediated signal transduction.
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:delta, 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.
Barbieri
M Alejandro
MA
Department of Cell Biology and Physiology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
Fernandez-Pol
Sebastian
S
Hunker
Christine
C
Horazdovsky
Bruce H
BH
Stahl
Philip D
PD
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D019938:Cyclin D1 / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490451:Rin1 protein, mouse; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins