Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics

Nat Cell Biol. 1999 Sep;1(5):253-9. doi: 10.1038/12963.

Abstract

Extracellular signals regulate actin dynamics through small GTPases of the Rho/Rac/Cdc42 (p21) family. Here we show that p21-activated kinase (Pak1) phosphorylates LIM-kinase at threonine residue 508 within LIM-kinase's activation loop, and increases LIM-kinase-mediated phosphorylation of the actin-regulatory protein cofilin tenfold in vitro. In vivo, activated Rac or Cdc42 increases association of Pak1 with LIM-kinase; this association requires structural determinants in both the amino-terminal regulatory and the carboxy-terminal catalytic domains of Pak1. A catalytically inactive LIM-kinase interferes with Rac-, Cdc42- and Pak1-dependent cytoskeletal changes. A Pak1-specific inhibitor, corresponding to the Pak1 autoinhibitory domain, blocks LIM-kinase-induced cytoskeletal changes. Activated GTPases can thus regulate actin depolymerization through Pak1 and LIM-kinase.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / physiology*
  • Animals
  • COS Cells
  • Cell Line
  • Cell Membrane / physiology
  • Cell Membrane / ultrastructure
  • Cytoskeleton / physiology*
  • Enzyme Activation
  • Humans
  • Kinetics
  • Lim Kinases
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • Signal Transduction
  • Transfection
  • Zinc Fingers
  • cdc42 GTP-Binding Protein / metabolism*
  • p21-Activated Kinases
  • rac GTP-Binding Proteins / metabolism*

Substances

  • Actins
  • Recombinant Proteins
  • Phosphothreonine
  • Protein Kinases
  • LIMK1 protein, human
  • Lim Kinases
  • PAK1 protein, human
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins