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Cell surface receptors activate p21-activated kinase 1 via multiple Ras and PI3-kinase-dependent pathways

Raymond E Menard1, Raymond R Mattingly

  • 1Department of Pharmacology, Wayne State University, 540 E. Canfield, Room 6326, Detroit, MI 48201, USA.

Cellular Signalling
|October 25, 2003
PubMed

Insights

p21-activated kinases (PAKs) are crucial serine-threonine protein kinases. This study reveals multiple pathways, including Ras-dependent ones, activate PAK1 using various agonists like LPA and EGF.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • p21-activated kinases (PAKs) are mammalian Ste20-like serine-threonine protein kinases.
  • PAK1 is implicated in various cellular processes, but its activation mechanisms are complex.

Purpose of the Study:

  • To elucidate the diverse signaling pathways that regulate PAK1 activation.
  • To investigate the roles of small GTPases (Ras, Rac, Cdc42, RhoA) and upstream kinases in PAK1 stimulation.

Main Methods:

  • Stimulation of PAK1 using agonists: carbachol, lysophosphatidic acid (LPA), epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA).
  • Utilized dominant-negative and active forms of Ras, Rac, and Cdc42 to assess their roles in PAK1 activation.
  • Employed inhibitors for EGF receptor tyrosine kinase, phosphatidylinositol 3-kinase (PI3-kinase), and protein kinase C (PKC).

Main Results:

  • PAK1 activation by all tested agonists was inhibited by dominant-negative Ras, Rac, and Cdc42.
  • Active Rac1 and Cdc42 independently induced maximal PAK1 activation.
  • EGF-induced PAK1 activation involved PI3-kinase, while muscarinic receptor stimulation was EGF-R-dependent.
  • LPA-mediated PAK1 activation was independent of PI3-kinase and EGF receptor but sensitive to RhoA inhibition.
  • Multiple Ras-dependent pathways contribute to PAK1 activation.

Conclusions:

  • PAK1 activation is orchestrated by multiple, converging, and diverging signaling pathways.
  • Small GTPases Rac and Cdc42 play critical roles in PAK1 activation.
  • Specific agonists utilize distinct upstream signaling cascades to modulate PAK1 activity.

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