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Rac1/p21-activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor

Natalia Zaldua1,2, Francisco Llavero3,4, Alain Artaso3

  • 1Center for Cooperative Research in Biosciences, Bizkaia Science and Technology Park, Spain.

The FEBS Journal
|December 15, 2015
PubMed

Insights

The Vav3/Rac pathway is crucial for B cell proliferation by regulating retinoblastoma protein (RB) phosphorylation and E2F activation. Targeting p21-activated kinase (PAK) and protein kinase Cε (PKCε) may inhibit uncontrolled B cell growth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Small GTPases, including Ras superfamily members, can activate E2F-dependent transcription, promoting cell proliferation.
  • The precise molecular mechanisms underlying this process, particularly involving the Vav/Rac signaling cascade in B cells, remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the Vav/Rac signaling cascade in B cell proliferation.
  • To elucidate the molecular mechanisms by which B cell receptor activation triggers proliferation, focusing on the Vav3 pathway.

Main Methods:

  • Utilized immortalized chicken DT40 B cell lines, including Vav3 knockout models.
  • Employed pharmacological and genetic approaches to identify upstream signaling molecules and downstream effectors.
  • Analyzed retinoblastoma protein (RB) phosphorylation and E2F activation.
  • Investigated the dependency on p21-activated kinase (PAK) and protein kinase Cε (PKCε) activities using Rac1 effector mutants.

Main Results:

  • Vav3 deficiency significantly reduced B cell proliferation upon B cell receptor activation.
  • Absence of Vav3 prevented RB phosphorylation and subsequent E2F activation.
  • Phosphatidylinositol-3-kinase and phospholipase Cγ2 (PLCγ2) were identified as key upstream regulators of the Vav3/Rac pathway.
  • Restoration of Vav3/Rac pathway signaling components rescued RB-E2F complex activation and cellular proliferation in knockout cells.
  • RB-E2F complex activation was dependent on PAK and PKCε, independent of actin cytoskeleton reorganization and Ras activity.

Conclusions:

  • The Vav3/Rac pathway, regulated by phosphatidylinositol-3-kinase and PLCγ2, is essential for RB phosphorylation and E2F-mediated proliferation in B cells.
  • PAK1 and PKCε are critical downstream effectors in the Vav/Rac pathway controlling B cell proliferation.
  • PAK1 and PKCε represent potential therapeutic targets for inhibiting aberrant B cell proliferation driven by the Vav/Rac pathway.
Keywords:
E2FRac1Vavp21 activated kinaseretinoblastoma protein

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