Characterization of a novel member of the DOK family that binds and modulates Abl signaling.
A novel member of the p62(dok) family of proteins, termed DOKL, is described. DOKL contains features of intracellular signaling molecules, including an N-terminal PH (pleckstrin homology) domain, a central PTB (phosphotyrosine binding) domain, and a C-terminal domain with multiple potential tyrosine phosphorylation sites and proline-rich regions, which might serve as ... docking sites for SH2- and SH3-containing proteins. The DOKL gene is predominantly expressed in bone marrow, spleen, and lung, although low-level expression of the RNA can also be detected in other tissues. DOKL and p62(dok) bind through their PTB domains to the Abelson tyrosine kinase in a kinase-dependent manner in both yeast and mammalian cells. DOKL is phosphorylated by the Abl tyrosine kinase in vivo. In contrast to p62(dok), DOKL lacks YxxP motifs in the C terminus and does not bind to Ras GTPase-activating protein (RasGAP) upon phosphorylation. Overexpression of DOKL, but not p62(dok), suppresses v-Abl-induced mitogen-activated protein (MAP) kinase activation but has no effect on constitutively activated Ras- and epidermal growth factor-induced MAP kinase activation. The inhibitory effect requires the PTB domain of DOKL. Finally, overexpression of DOKL in NIH 3T3 cells inhibits the transforming activity of v-Abl. These results suggest that DOKL may modulate Abl function.
Mesh Terms:
3T3 Cells, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Line, Transformed, Cell Transformation, Neoplastic, DNA, Complementary, DNA-Binding Proteins, Enzyme Activation, Fusion Proteins, bcr-abl, Humans, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Oncogene Proteins v-abl, Phosphoproteins, Phosphorylation, RNA-Binding Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Subcellular Fractions, Tissue Distribution, Tyrosine
3T3 Cells, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Line, Transformed, Cell Transformation, Neoplastic, DNA, Complementary, DNA-Binding Proteins, Enzyme Activation, Fusion Proteins, bcr-abl, Humans, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Oncogene Proteins v-abl, Phosphoproteins, Phosphorylation, RNA-Binding Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Subcellular Fractions, Tissue Distribution, Tyrosine
Mol. Cell. Biol.
Date: Dec. 01, 1999
PubMed ID: 10567556
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