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Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on

M Zhao1, A A Schmitz, Y Qin

  • 1Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

The Journal of Experimental Medicine
|August 8, 2001
PubMed

Insights

p62(dok) acts as a negative regulator in growth factor signaling. Its plasma membrane recruitment, dependent on PI3-kinase, is crucial for suppressing cell proliferation and MAPK activity.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Signal transduction

Background:

  • Growth factors regulate cell proliferation via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) pathway.
  • p62(dok) is an adaptor protein identified as a regulator of this pathway.

Purpose of the Study:

  • To investigate the role of p62(dok) in regulating growth factor-induced cell proliferation and MAPK signaling.
  • To elucidate the mechanism of p62(dok) function, focusing on its plasma membrane recruitment.

Main Methods:

  • Utilized p62(dok)-deficient cells and reintroduction of p62(dok).
  • Assessed cell proliferation and MAPK activity.
  • Investigated the role of phosphoinositide 3-kinase (PI3-kinase) and the pleckstrin homology (PH) domain in p62(dok) translocation.
  • Examined p62(dok) interaction with RasGAP and Nck.

Main Results:

  • Reintroduction of p62(dok) suppressed increased cell proliferation and prolonged MAPK activity in deficient cells.
  • Plasma membrane recruitment of p62(dok) was essential for its negative regulatory function.
  • PDGF-triggered p62(dok) translocation required PI3-kinase activation and PH domain binding to phosphoinositides.
  • p62(dok) exerted its negative effect independently of RasGAP and Nck association.

Conclusions:

  • p62(dok) functions as a negative regulator of the PDGF receptor (PDGFR)/Ras/MAPK signaling pathway.
  • PI3-kinase-dependent recruitment of p62(dok) to the plasma membrane is a key mechanism for its function.

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