The multi-adaptor proto-oncoprotein Cbl is a key regulator of Rac and actin assembly.
The induction of protein tyrosine kinase signaling pathways is a principal mechanism for promoting cellular activation. Biochemical and genetic analyses have implicated the multi-adaptor proto-oncogene protein Cbl as a key negative regulator of activated protein tyrosine kinases. By inhibiting the function of Cbl as a multi-domain adaptor protein, through expression of a truncated form (480-Cbl), we demonstrate that Cbl is a potent negative regulator of actin assembly in response to receptor tyrosine kinase (RTK) activation. Expression of 480-Cbl dramatically enhances RTK-dependent induction of actin dorsal ruffles, which correlates with a pronounced increase in Rac activation. By contrast, mitogenic signaling by RTK targets, such as PI 3-kinase and MAP kinases, as well as RTK-mediated tyrosine phosphorylation do not appear to be affected by 480-Cbl expression. Further, we determined that Cbl undergoes a striking RTK-activation-dependent translocation to sites of active actin dorsal ruffle nucleation. Hence, the selective regulation of RTK signaling to the actin cytoskeleton appears to result from recruitment of signaling proteins on a Cbl template bound to the actin cytoskeleton.
Scaife
Robin M
RM
Department of Pathology, University of Western Australia, QE II Medical Centre, Crawley WA 6009, Australia. rascaife@cyllene.uwa.edu.au
Courtneidge
Sara A
SA
Langdon
Wallace Y
WY
D016475:3T3 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D005057:Eukaryotic Cells / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D050722:Oncogene Protein v-cbl; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D050722:Oncogene Protein v-cbl; D020033:Protein Isoforms; D015682:Retroviridae Proteins, Oncogenic; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020744:rac GTP-Binding Proteins