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PAK kinase regulates Rac GTPase and is a potential target in human schwannomas

Christine Flaiz1, Jonathan Chernoff, Sylwia Ammoun

  • 1Clinical Neurobiology, Peninsula College for Medicine and Dentistry, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.

Experimental Neurology
|May 5, 2009
PubMed

Insights

Merlin loss causes nervous system tumors. Researchers found p21-activated kinase (PAK) acts upstream of Rac, controlling cell adhesion and spreading in schwannoma cells, suggesting PAK as a therapeutic target.

Area of Science:

  • Neuro-oncology
  • Cellular signaling
  • Molecular biology

Background:

  • Merlin loss leads to benign nervous system tumors like schwannomas.
  • Schwannomas exhibit increased Rac1/Cdc42 activity, p21-activated kinase 2 (PAK2) activation, and altered cell adhesion.
  • PAK's role in the Rac pathway is not fully understood, yet PAK is a potential therapeutic target for schwannomas.

Purpose of the Study:

  • To investigate the role of PAK activation in Rac1/Cdc42 activity, cell spreading, and adhesion.
  • To characterize PAK's position within the Rac pathway in human primary schwannoma and Schwann cells.

Main Methods:

  • Utilized a novel small-molecule PAK inhibitor, IPA-3.
  • Examined the effects of IPA-3 on PAK2 activation, its interaction with Pix, and subsequent Rac1 activation.
  • Assessed cell spreading and adhesion in IPA-3 treated schwannoma and Schwann cells.

Main Results:

  • IPA-3 inhibited PAK2 activation at Ser192/197, disrupting the PAK-Pix interaction.
  • IPA-3 treatment decreased Pix-mediated Rac1 activation, indicating PAK acts upstream of Rac.
  • Rac activation at focal adhesions is crucial for cell spreading and adhesion in both Schwann and schwannoma cells.

Conclusions:

  • PAK functions upstream of Rac in the signaling pathway regulating cell adhesion and spreading.
  • These findings clarify PAK's role in the Rac pathway and support its potential as a therapeutic target for schwannomas.

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