Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling.
Dok-1 is an adaptor protein that is a substrate for Bcr-Abl and other tyrosine protein kinases. The presence of pleckstrin homology and phosphotyrosine binding domains as well as multiple tyrosine phosphorylation sites suggests that Dok-1 is involved in protein-protein and/or protein-lipid interactions. Here we show that stimulation of Mo7 hematopoietic ... cells with c-Kit ligand (KL) induces phosphatidylinositol (PI) 3-kinase-dependent tyrosine phosphorylation and membrane recruitment of Dok-1. Addition of the K-Ras membrane-targeting motif to Dok-1 generated a constitutively membrane-bound Dok-1 protein whose tyrosine phosphorylation was independent of PI 3-kinase. Membrane localization of Dok-1 was required for its ability to function as a negative regulator of cell proliferation. Additional experiments revealed that Dok-1 associated with the juxtamembrane region and C-terminal tail of c-Kit. Lyn promoted phosphorylation of c-Kit and association of c-Kit and Dok-1. Both Lyn and Tec were capable of phosphorylating Dok-1. However, the use of primary bone marrow mast cells from normal and Lyn-deficient mice demonstrated that Lyn is required for KL-dependent Dok-1 tyrosine phosphorylation. Taken together, these data indicate that activation of PI 3-kinase by KL promotes binding of the Dok pleckstrin homology domain and Dok-1 recruitment to the plasma membrane where Dok-1 is phosphorylated by Src and/or Tec family kinases.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Androstadienes, Animals, COS Cells, Cell Division, Cell Line, Cell Membrane, DNA, Complementary, DNA-Binding Proteins, Enzyme Inhibitors, Glutathione Transferase, Humans, Lipid Metabolism, Mice, Phosphoproteins, Phosphorylation, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), RNA-Binding Proteins, Recombinant Fusion Proteins, Signal Transduction, Subcellular Fractions, Transfection, Tyrosine, src-Family Kinases
1-Phosphatidylinositol 3-Kinase, Androstadienes, Animals, COS Cells, Cell Division, Cell Line, Cell Membrane, DNA, Complementary, DNA-Binding Proteins, Enzyme Inhibitors, Glutathione Transferase, Humans, Lipid Metabolism, Mice, Phosphoproteins, Phosphorylation, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), RNA-Binding Proteins, Recombinant Fusion Proteins, Signal Transduction, Subcellular Fractions, Transfection, Tyrosine, src-Family Kinases
J. Biol. Chem.
Date: Apr. 19, 2002
PubMed ID: 11825908
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