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First published online 4 December 2002
doi: 10.1242/jcs.00244
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Research Article |
1 Department of Pathology, University of Western Australia, QE II Medical
Centre, Crawley WA 6009, Australia
2 Van Andel Research Institute, Grand Rapids, MI 49503, USA
* Author for correspondence (e-mail: rscaife{at}cyllene.uwa.edu.au)
Accepted 28 October 2002
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.
Key words: Actin, Cbl, Rac, RTK, Src
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