Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling

被引:44
作者
Liang, XQ
Wisniewski, D
Strife, A
Shivakrupa
Clarkson, B
Resh, MD
机构
[1] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Therapeut Program, New York, NY 10021 USA
[3] NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Basic Res Lab, Frederick, MD 21702 USA
[4] NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Immunobiol Lab, Frederick, MD 21702 USA
关键词
D O I
10.1074/jbc.M200277200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 e-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.
引用
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页码:13732 / 13738
页数:7
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