Phosphoinositide 3-kinase-dependent membrane recruitment of p62dok is essential for its negative effect on mitogen-activated protein (MAP) kinase activation

M. Zhao, A. A.P. Schmitz, Y. Qin, A. Di Cristofano, P. P. Pandolfi, L. Van Aelst

Research output: Contribution to journalArticle

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)265-274
Number of pages10
JournalJournal of Experimental Medicine
Volume194
Issue number3
DOIs
StatePublished - Aug 6 2001

Keywords

  • Cell proliferation
  • Growth factors
  • Membrane lipids
  • Protein-serine-threonine kinase
  • Signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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