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The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras

Concepcion Jimenez1, Carmen Hernandez, Belen Pimentel

  • 1Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Universidad Autónoma de Madrid, Cantoblanco, Spain.

The Journal of Biological Chemistry
|August 28, 2002
PubMed

Insights

Class IA phosphoinositide 3-kinase (PI3K) regulation involves a p85 subunit inhibiting the p110 catalytic subunit. Tyr kinase stimulation releases this inhibition, enabling Ras-induced PI3K activation for cell responses.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Class IA phosphoinositide 3-kinase (PI3K) is crucial for cell division and survival.
  • PI3K activation is triggered by tyrosine (Tyr) kinase stimulation and Ras proteins.

Purpose of the Study:

  • To investigate the role of the p85 regulatory subunit in modulating PI3K activation by Ras.
  • To elucidate the mechanism by which Tyr kinase stimulation influences Ras-mediated PI3K activation.

Main Methods:

  • Utilized p85 deletion mutants to assess the impact on p110 activity.
  • Examined PI3K activation in response to active Ras and Tyr-phosphorylated peptides mimicking activated platelet-derived growth factor receptor.

Main Results:

  • The C-terminal region of p85, including the C-Src homology 2 (C-SH2) domain, inhibits Ras-induced activation of the p110 catalytic subunit.
  • A p85 deletion mutant showed significantly increased p110 activity with active Ras.
  • Purified wild-type p85-p110 exhibited only slight stimulation by active Ras, but Tyr kinase stimulation restored this response.

Conclusions:

  • The p85 subunit acts as an inhibitor of Ras-induced p110 activation.
  • Tyr kinase stimulation is essential for releasing the inhibitory effect of p85, thereby enabling Ras-mediated PI3K activation.
  • This highlights a regulatory mechanism where Tyr kinase signaling converges with Ras signaling to control class IA PI3K activity.

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