Phosphopleckstrin Inhibits Gβγ-activable Platelet Phosphatidylinositol-4,5-bisphosphate 3-Kinase*

Pleckstrin, the prototypic protein containing two copies of the pleckstrin homology domain, is a prominent substrate of protein kinase C in platelets and neutrophils. Both cell types have p85 subunit-containing phosphoinositide 3-kinase (p85/PI3K) and non-p85-containing PI3K (PI3Kγ) that is activated by βγ subunits of heterotrimeric GTP-binding proteins. We have shown that a PI3K product, phosphatidylinositol (PI) 3,4,5-trisphosphate, promotes pleckstrin phosphorylation in platelets. Since pleckstrin homology domains are thought to interact with Gβγ heterodimers and/or PI(4,5)P2, we have examined the effects of recombinant pleckstrins on platelet PI3Kγ and p85/PI3K activities. Depending upon its phosphorylation/charged state, pleckstrin inhibits PI3Kγ, but not p85/PI3K. Pleckstrin-mediated inhibition of PI3Kγ is overcome by excess Gβγ and is restricted to PI(4,5)P2 as substrate, i.e. pleckstrin does not inhibit phosphorylation of PI(4)P or PI. Consistent with this, activation of protein kinase C by exposure of platelets to β-phorbol diester (to increase endogenous pleckstrin phosphorylation) prior to platelet lysis causes inhibition of Gβγ-stimulatable PI3K activity only with respect to PI(4,5)P2 substrate. This phosphopleckstrin-mediated inhibition is overcome by increasing concentrations of Gβγ. We propose that phosphorylation of pleckstrin may constitute an important inhibitory mechanism for PI3Kγ-mediated cell signaling.

• Publication year

  1996

• Venue

  Journal of Biological Chemistry

• Publication date

  1996-10-11

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.271.41.25192PMID 8810277
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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