Tyrosine phosphorylation of p62(Dok) 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 (DokDeltaPH) that lacked its pleckstrin homology domain failed to undergo tyrosine phosphorylation in response to cell adhesion or insulin. Furthermore, unlike the wild-type protein, DokDeltaPH 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 DokDeltaPH 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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Base Sequence, Binding Sites, CHO Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion, Cell Movement, Cricetinae, DNA Primers, DNA-Binding Proteins, Enzyme Activation, Gene Expression, Humans, Insulin, Mice, Oncogene Proteins, Phosphoproteins, Phosphorylation, RNA-Binding Proteins, Subcellular Fractions, Tyrosine, src-Family Kinases
Adaptor Proteins, Signal Transducing, Animals, Base Sequence, Binding Sites, CHO Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion, Cell Movement, Cricetinae, DNA Primers, DNA-Binding Proteins, Enzyme Activation, Gene Expression, Humans, Insulin, Mice, Oncogene Proteins, Phosphoproteins, Phosphorylation, RNA-Binding Proteins, Subcellular Fractions, Tyrosine, src-Family Kinases
EMBO J.
Date: Apr. 01, 1999
PubMed ID: 10202139
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