A PLCβ/PI3Kγ-GSK3 signaling pathway regulates cofilin phosphatase slingshot2 and neutrophil polarization and chemotaxis

Dev Cell. 2011 Dec 13;21(6):1038-50. doi: 10.1016/j.devcel.2011.10.023.

Abstract

Neutrophils, in response to a chemoattractant gradient, undergo dynamic F-actin remodeling, a process important for their directional migration or chemotaxis. However, signaling mechanisms for chemoattractants to regulate the process are incompletely understood. Here, we characterized chemoattractant-activated signaling mechanisms that regulate cofilin dephosphorylation and actin cytoskeleton reorganization and are critical for neutrophil polarization and chemotaxis. In neutrophils, chemoattractants induced phosphorylation and inhibition of GSK3 via both PLCβ-PKC and PI3Kγ-AKT pathways, leading to the attenuation of GSK3-mediated phosphorylation and inhibition of the cofilin phosphatase slingshot2 and an increase in dephosphorylated, active cofilin. The relative contribution of this GSK3-mediated pathway to neutrophil chemotaxis regulation depended on neutrophil polarity preset by integrin-induced polarization of PIP5K1C. Therefore, our study characterizes a signaling mechanism for chemoattractant-induced actin cytoskeleton remodeling and elucidates its context-dependent role in regulating neutrophil polarization and chemotaxis.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors / metabolism*
  • Actins / metabolism
  • Animals
  • Base Sequence
  • Cell Movement / physiology
  • Cell Polarity / physiology
  • Chemotaxis, Leukocyte / physiology
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism*
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3 / deficiency
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • In Vitro Techniques
  • Integrins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neutrophils / physiology*
  • Phospholipase C beta / deficiency
  • Phospholipase C beta / genetics
  • Phospholipase C beta / metabolism*
  • Phosphoprotein Phosphatases / deficiency
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Signal Transduction

Substances

  • Actin Depolymerizing Factors
  • Actins
  • Integrins
  • RNA, Small Interfering
  • Phosphotransferases (Alcohol Group Acceptor)
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • Glycogen Synthase Kinase 3
  • Phosphoprotein Phosphatases
  • Phospholipase C beta