Tyrosine phosphorylation of p62Dok induced by cell adhesion and insulin: possible role in cell migration

Dok, a 62‐kDa Ras GTPase‐activating protein (rasGAP)‐associated phosphotyrosyl protein, is thought to act as a multiple docking protein downstream of receptor or non‐receptor tyrosine kinases. Cell adhesion to extracellular matrix proteins induced marked tyrosine phosphorylation of Dok. This adhesion‐dependent phosphorylation of Dok was mediated, at least in part, by Src family tyrosine kinases. The maximal insulin‐induced tyrosine phosphorylation of Dok required a Src family kinase. A mutant Dok (DokΔPH) that lacked its pleckstrin homology domain failed to undergo tyrosine phosphorylation in response to cell adhesion or insulin. Furthermore, unlike the wild‐type protein, DokΔPH did not localize to subcellular membrane components. Insulin promoted the association of tyrosine‐phosphorylated Dok with the adapter protein NCK and rasGAP. In contrast, a mutant Dok (DokY361F), in which Tyr361 was replaced by phenylalanine, failed to bind NCK but partially retained the ability to bind rasGAP in response to insulin. Overexpression of wild‐type Dok, but not that of DokΔPH or DokY361F, enhanced the cell migratory response to insulin without affecting insulin activation of mitogen‐activated protein kinase. These results identify Dok as a signal transducer that potentially links, through its interaction with NCK or rasGAP, cell adhesion and insulin receptors to the machinery that controls cell motility.

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