GPCR-mediated PLCβγ/PKCβ/PKD signaling pathway regulates the cofilin phosphatase slingshot 2 in neutrophil chemotaxis

Mol Biol Cell. 2015 Mar 1;26(5):874-86. doi: 10.1091/mbc.E14-05-0982. Epub 2015 Jan 7.

Abstract

Chemotaxis requires precisely coordinated polymerization and depolymerization of the actin cytoskeleton at leading fronts of migrating cells. However, GPCR activation-controlled F-actin depolymerization remains largely elusive. Here, we reveal a novel signaling pathway, including Gαi, PLC, PKCβ, protein kinase D (PKD), and SSH2, in control of cofilin phosphorylation and actin cytoskeletal reorganization, which is essential for neutrophil chemotaxis. We show that PKD is essential for neutrophil chemotaxis and that GPCR-mediated PKD activation depends on PLC/PKC signaling. More importantly, we discover that GPCR activation recruits/activates PLCγ2 in a PI3K-dependent manner. We further verify that PKCβ specifically interacts with PKD1 and is required for chemotaxis. Finally, we identify slingshot 2 (SSH2), a phosphatase of cofilin (actin depolymerization factor), as a target of PKD1 that regulates cofilin phosphorylation and remodeling of the actin cytoskeleton during neutrophil chemotaxis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Animals
  • Chemotaxis, Leukocyte / immunology*
  • Cofilin 1 / metabolism*
  • Female
  • Humans
  • Male
  • Mice
  • Neutrophils / enzymology
  • Neutrophils / immunology
  • Neutrophils / physiology*
  • Phospholipase C beta / metabolism
  • Phospholipase C gamma / metabolism
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Kinase C / metabolism
  • Protein Kinase C beta / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction* / immunology

Substances

  • Cofilin 1
  • Receptors, G-Protein-Coupled
  • protein kinase D
  • Protein Kinase C
  • Protein Kinase C beta
  • Phosphoprotein Phosphatases
  • slingshot phosphatase 2, human
  • Phospholipase C beta
  • Phospholipase C gamma