Rac1 links leading edge and uropod events through Rho and myosin activation during chemotaxis

Blood. 2006 Oct 15;108(8):2814-20. doi: 10.1182/blood-2006-01-010363. Epub 2006 Jun 29.

Abstract

Chemotactic responsiveness is crucial to neutrophil recruitment to sites of infection. During chemotaxis, highly divergent cytoskeletal programs are executed at the leading and trailing edge of motile neutrophils. The Rho family of small GTPases plays a critical role in cell migration, and recent work has focused on elucidating the specific roles played by Rac1, Rac2, Cdc42, and Rho during cellular chemotaxis. Rac GTPases regulate actin polymerization and extension of the leading edge, whereas Rho GTPases control myosin-based contraction of the trailing edge. Rac and Rho signaling are thought to crosstalk with one another, and previous research has focused on mutual inhibition of Rac and Rho signaling during chemotaxis. Indeed, polarization of neutrophils has been proposed to involve the activity of a negative feedback system where Rac activation at the front of the cell inhibits local Rho activation, and vice versa. Using primary human neutrophils and neutrophils derived from a Rac1/Rac2-null transgenic mouse model, we demonstrate here that Rac1 (and not Rac2) is essential for Rho and myosin activation at the trailing edge to regulate uropod function. We conclude that Rac plays both positive and negative roles in the organization of the Rhomyosin "backness" program, thereby promoting stable polarity in chemotaxing neutrophils.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity
  • Chemotaxis, Leukocyte / physiology*
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myosin Light Chains / metabolism
  • Myosins / metabolism*
  • Neuropeptides / deficiency
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Neutrophils / metabolism
  • Neutrophils / physiology*
  • Neutrophils / ultrastructure
  • RAC2 GTP-Binding Protein
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transduction, Genetic
  • rac GTP-Binding Proteins / deficiency
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism*
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Myosin Light Chains
  • Neuropeptides
  • Rac1 protein, mouse
  • Recombinant Proteins
  • Myosins
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein