Translocation of CrkL to focal adhesions mediates integrin-induced migration downstream of Src family kinases.
The adapter protein Crk-Like (CrkL) can associate with the Src substrate p130(Cas) (Cas). The biological role of CrkL downstream of Cas, however, has been largely obscure. Consistent with the ability of CrkL to biochemically associate with Cas, we found that Src triggers translocation of CrkL to focal adhesions (FAs) in a manner dependent on Cas. Forced localization of CRKL to FAs (FA-CRKL) by itself was sufficient to induce activation of Rac1 and Cdc42 and rescued haptotaxis defects of mouse embryonic fibroblasts (MEFs) lacking Src, Yes, and Fyn, three broadly expressed Src family members required for integrin-induced migration. Consistent with Rac1 activation, FA-CRKL induced cotranslocation of a Rac1 activator, Dock1, to focal adhesions. These results therefore indicate a role for CrkL in mediating Src signaling by activating small G proteins at focal adhesions. Furthermore, MEFs lacking CrkL show impaired integrin-induced migration despite expression of a closely related protein, Crk-II, in these cells. These results therefore provide formal evidence that CrkL plays a specific role in integrin-induced migration as a downstream mediator of Src.
Li
Leiming
L
Committee on Cell Physiology and The Ben May Institute for Cancer Research and Center for Molecular Oncology, The University of Chicago, Chicago, Illinois 60637, USA.
Guris
Deborah L
DL
Okura
Masaya
M
Imamoto
Akira
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D022001:Focal Adhesions / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D016023:Integrins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D019061:src-Family Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein