The Tom1L1-clathrin heavy chain complex regulates membrane partitioning of the tyrosine kinase Src required for mitogenic and transforming activities.
Compartmentalization of Src tyrosine kinases (SFK) plays an important role in signal transduction induced by a number of extracellular stimuli. For example, Src mitogenic signaling induced by platelet-derived growth factor (PDGF) is initiated in cholesterol-enriched microdomain caveolae. How this Src subcellular 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.
Collin
Guillaume
G
CNRS UMR5237, University of Montpellier 1 and 2, CRBM, 1919 route de Mende, 34293 Montpellier Cedex 05, France.
Franco
Mélanie
M
Simon
Valérie
V
Bénistant
Christine
C
Roche
Serge
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D021941:Caveolae / Q000201:enzymology; D002462:Cell Membrane / Q000201:enzymology*; D002471:Cell Transformation, Neoplastic; D033922:Clathrin Heavy Chains / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D041681:NIH 3T3 Cells; D021381:Protein Transport; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*