Abl functions as a negative regulator of Met-induced cell motility via phosphorylation of the adapter protein CrkII.
HGF, the ligand for the Met receptor tyrosine kinase, is a potent modulator of epithelial-mesenchymal transition and dispersal of epithelial cells, which are processes that play a crucial role in cell motility during normal development and malignant transformation. We and others have shown earlier that the adapter protein CrkII and its associated proteins positively regulate cell migratory events in response to both haptotactic and chemotactic stimuli, including HGF. Here, we demonstrate for the first time that phosphorylation of CrkII serves as a negative feedback loop to regulate motile responses upon Met stimulation. Thus, we found that the treatment of cells with HGF induces tyrosine phosphorylation of CrkII at Y221, which in turn results in inhibition of CrkII signaling via formation of an intramolecular pY221-SH2-domain interaction. Accordingly, expression of a mutant form of CrkII, CrkII-Y221F, which is resistant to phosphorylation at this negative regulatory site, enhanced Met-induced cell motility. Furthermore, we demonstrate here that the Met-induced CrkII phosphorylation depends on the Abl tyrosine kinase activity. As a corollary, we found that Abl inhibitors, such as the STI571 compound, significantly enhanced Met-induced cell motility, but failed to do so in cells that expressed the CrkII-Y221F mutant protein. Taken together, these results demonstrate that the Abl tyrosine kinase functions as a negative regulator of Met-induced cell migration, and that it does so by inducing CrkII phosphorylation at the site Y221.
Cipres
Angel
A
Cancer Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA, USA.
Abassi
Yama A
YA
Vuori
Kristiina
K
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D025461:Feedback, Physiological / Q000235:genetics*; D016313:Genes, abl; D006367:HeLa Cells; D006801:Humans; D008715:Methionine / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D050737:Proto-Oncogene Proteins c-crk / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D050737:Proto-Oncogene Proteins c-crk; D014443:Tyrosine; D008715:Methionine