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Mol. Cell. Biol. doi:10.1128/MCB.00543-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The Tom1L1-Clathrin Heavy Chain complex regulates membrane partitioning of the tyrosine kinase Src required for mitogenic and transforming activities

CNRS UMR5237 University of Montpellier 1 and 2, CRBM, 1919 route de Mende, 34293 Montpellier, France

^* To whom correspondence should be addressed. Email: Serge.Roche{at}crbm.cnrs.fr.

	Abstract

Compartmentalization of Src tyrosine kinases (SFK) plays an important role for signal transduction induced by a number of extracellular stimuli. For example, Src mitogenic signaling induced by the growth factor Platelet-Derived Growth Factor (PDGF) is initiated in cholesterol-enriched microdomains caveolae. How this Src sub-cellular localization is regulated is largely unknown. Here we show that the Tom1L1-Clathrin Heavy Chain (CHC) complex negatively regulates the level of SFK in caveolae needed for the induction of DNA synthesis. Tom1L1 is both an interactor and a substrate of SFK. Intriguingly, it stimulates Src activity without promoting mitogenic signaling. We found that, upon association with CHC, Tom1L1 reduced the level of SFK in caveolae, thereby preventing its association with the PDGF receptor, which is required for the induction of mitogenesis. Similarly, the Tom1L1-CHC complex reduced also the level of oncogenic Src in cholesterol-enriched microdomains, thus affecting both its capacity to induce DNA synthesis and cell transformation. Conversely, Tom1L1, when not associated with CHC, accumulated in caveolae and promoted Src-driven DNA synthesis. We concluded that the Tom1L1-CHC complex defines a novel mechanism involved in negative regulation of mitogenic and transforming signals, by modulating SFK partitioning at the plasma membrane.