Original Article

Phosphoinositide 3-Kinase–dependent Membrane Recruitment of p62^dok Is Essential for Its Negative Effect on Mitogen-activated Protein (MAP) Kinase Activation

Correspondence to: Linda Van Aelst, Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724. Tel:516-367-6829 Fax:516-367-8815 E-mail:vanaelst{at}cshl.org.

A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62^dok, the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62^dok-deficient cells, that p62^dok acts as a negative regulator of growth factor–induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62^dok into p62^dok-^/- cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62^dok is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62^dok requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3'-phosphorylated phosphoinositides. Furthermore, we demonstrate that p62^dok can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62^dok functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase–dependent recruitment of p62^dok to the plasma membrane.

Key Words: growth factors, cell proliferation, membrane lipids, signal transduction, protein-serine-threonine kinase

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