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J. Exp. Med. 194 (3): 265-274

Copyright © 2001 by the Rockefeller University Press.

Original Article

Phosphoinositide 3-Kinase–Dependent Membrane Recruitment of P62dok Is Essential for Its Negative Effect on Mitogen-Activated Protein (Map) Kinase Activation

Mingming Zhaoa,b, Arndt A.P. Schmitza, Yi Qina, Antonio Di Cristofanoc, Pier Paolo Pandolfic, , and Linda Van Aelsta,b

a Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
b Molecular and Cell Biology Graduate Program, State University of New York at Stony Brook, Stony Brook, New York 11733
c Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
Cold Spring Harbor Laboratory, 1 Bungtown Rd., Cold Spring Harbor, NY 11724.516-367-8815516-367-6829

vanaelst{at}cshl.org

Abstract: 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 p62dok, the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62dok-deficient cells, that p62dok acts as a negative regulator of growth factor–induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62dok into p62dok–/– cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62dok is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62dok requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3'-phosphorylated phosphoinositides. Furthermore, we demonstrate that p62dok can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62dok functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase–dependent recruitment of p62dok to the plasma membrane.

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

A. Di Cristofano's present address is Human Genetics Program, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111.

Abbreviations used in this paper: aa, amino acid(s); MAPK, mitogen-activated protein kinase; MEF, mouse embryo fibroblast; MLV, multilamellar vesicle; PC, phosphatidylcholine; PDGFR, platelet-derived growth factor receptor; PH, pleckstrin homology; PS, phosphatidylserine; PTB, phosphotyrosine binding; RT, room temperature; RTK, receptor tyrosine kinase; SHIP1, Src homology 2 domain–containing inositol 5-phosphatase; WT, wild-type.

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