Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation

Zhao, M. M., Schmitz, A. A. P., Qin, Y., Di Cristofano, A., Pandolfi, P. P., Van Aelst, L. (August 2001) Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation. Journal of Experimental Medicine, 194 (3). pp. 265-274. ISSN 0022-1007

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URL: http://www.ncbi.nlm.nih.gov/pubmed/11489946
DOI: 10.1084/jem.194.3.265

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/niitogen-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 phosphomositides. 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 P13-kinase-dependent recruitment of p62(dok) to the plasma membrane.

Item Type: Paper
Uncontrolled Keywords: growth factors cell proliferation membrane lipids signal transduction protein-serine-threonine kinase B-CELL RECEPTOR TYROSINE PHOSPHORYLATION SIGNAL-TRANSDUCTION DOCKING PROTEIN BINDING DOK ASSOCIATION FAMILY GAP P56(DOK-2)
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > phosphoinositide 3-kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Van Aelst lab
Depositing User: Matt Covey
Date: August 2001
Date Deposited: 18 Dec 2013 22:00
Last Modified: 18 Dec 2013 22:00
PMCID: PMC2193463
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29097

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