Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis

Author:

Srinivasan Supriya1,Wang Fei1,Glavas Suzana1,Ott Alexander1,Hofmann Fred2,Aktories Klaus2,Kalman Daniel3,Bourne Henry R.1

Affiliation:

1. Department of Cellular and Molecular Pharmacology and Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA 94143

2. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, D-79104 Freiburg, Germany

3. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322

Abstract

Neutrophils exposed to chemoattractants polarize and accumulate polymerized actin at the leading edge. In neutrophil-like HL-60 cells, this asymmetry depends on a positive feedback loop in which accumulation of a membrane lipid, phosphatidylinositol (PI) 3,4,5-trisphosphate (PI[3,4,5]P3), leads to activation of Rac and/or Cdc42, and vice versa. We now report that Rac and Cdc42 play distinct roles in regulating this asymmetry. In the absence of chemoattractant, expression of constitutively active Rac stimulates accumulation at the plasma membrane of actin polymers and of GFP-tagged fluorescent probes for PI(3,4,5)P3 (the PH domain of Akt) and activated Rac (the p21-binding domain of p21-activated kinase). Dominant negative Rac inhibits chemoattractant-stimulated accumulation of actin polymers and membrane translocation of both fluorescent probes and attainment of morphologic polarity. Expression of constitutively active Cdc42 or of two different protein inhibitors of Cdc42 fails to mimic effects of the Rac mutants on actin or PI(3,4,5)P3. Instead, Cdc42 inhibitors prevent cells from maintaining a persistent leading edge and frequently induce formation of multiple, short lived leading edges containing actin polymers, PI(3,4,5)P3, and activated Rac. We conclude that Rac plays a dominant role in the PI(3,4,5)P3-dependent positive feedback loop required for forming a leading edge, whereas location and stability of the leading edge are regulated by Cdc42.

Publisher

Rockefeller University Press

Subject

Cell Biology

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