Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42

Cell. 2003 Jul 25;114(2):215-27. doi: 10.1016/s0092-8674(03)00559-2.

Abstract

Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Animals
  • COS Cells
  • Cell Polarity / drug effects
  • Chemotaxis
  • Chlorocebus aethiops
  • Complement C5a / pharmacology
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Transfection
  • cdc42 GTP-Binding Protein / metabolism*

Substances

  • Actins
  • Guanine Nucleotide Exchange Factors
  • Complement C5a
  • Protein-Serine-Threonine Kinases
  • Heterotrimeric GTP-Binding Proteins
  • cdc42 GTP-Binding Protein