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Published on: July 17, 2020

The p110delta isoform of PI 3-kinase negatively controls RhoA and PTEN

Evangelia A Papakonstanti1, Anne J Ridley, Bart Vanhaesebroeck

  • 1Ludwig Institute for Cancer Research, London, UK.

The EMBO Journal
|June 22, 2007
PubMed

Insights

The PI3K/PTEN pathway, crucial for tumor suppression, is bidirectional. PI3K signaling reciprocally controls PTEN activity through the RhoA/ROCK pathway, revealing a novel feedback loop.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Phosphoinositide 3-kinase (PI3K) signaling is vital for tumor suppression, primarily through the action of PTEN.
  • The PTEN-PI3K interaction was considered unidirectional, with PTEN lipid degradation controlling cell functions.

Purpose of the Study:

  • To investigate the reciprocal regulation between PI3K and PTEN.
  • To elucidate the role of PI3K in controlling PTEN activity and cellular processes.

Main Methods:

  • Investigated the impact of p110delta PI3K inactivation in macrophages.
  • Analyzed signaling pathways involving RhoA, Akt, Rac1, and PTEN.
  • Utilized pharmacological inhibition of ROCK (a RhoA effector kinase).

Main Results:

  • Inactivation of p110delta PI3K led to increased RhoA and PTEN activity, despite reduced Akt and Rac1 activation.
  • Increased RhoA-GTP levels were linked to p190RhoGAP inactivation and reduced RhoA binding to p27.
  • ROCK inhibition reversed signaling defects, including Akt phosphorylation, chemotaxis, and proliferation.

Conclusions:

  • The PI3K/PTEN relationship is bidirectional, with PI3K negatively regulating PTEN via the RhoA/ROCK pathway.
  • Identifies the RhoA/ROCK pathway as a key mediator of p110delta PI3K signaling.
  • Establishes a novel feedback loop where PI3K controls itself through PTEN regulation.

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