c-Abl tyrosine kinase regulates neutrophil crawling behavior under fluid shear stress via Rac/PAK/LIMK/cofilin signaling axis

J Cell Biochem. 2018 Mar;119(3):2806-2817. doi: 10.1002/jcb.26453. Epub 2017 Nov 20.

Abstract

The excessive recruitment and improper activation of polymorphonuclear neutrophils (PMNs) often induces serious injury of host tissues, leading to inflammatory disorders. Therefore, to understand the molecular mechanism on neutrophil recruitment possesses essential pathological and physiological importance. In this study, we found that physiological shear stress induces c-Abl kinase activation in neutrophils, and c-Abl kinase inhibitor impaired neutrophil crawling behavior on ICAM-1. We further identified Vav1 was a downstream effector phosphorylated at Y174 and Y267. Once activated, c-Abl kinase regulated the activity of Vav1, which further affected Rac1/PAK1/LIMK1/cofilin signaling pathway. Here, we demonstrate a novel signaling function and critical role of c-Abl kinase during neutrophil crawling under physiological shear by regulating Vav1. These findings provide a promising treatment strategy for inflammation-related disease by inactivation of c-Abl kinase to restrict neutrophil recruitment.

Keywords: c-Abl kinase; cytoskeletal rearrangement; neutrophil crawling; shear stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Depolymerizing Factors / metabolism*
  • Cell Movement*
  • Female
  • HEK293 Cells
  • Humans
  • Lim Kinases / metabolism*
  • Male
  • Neutrophils / cytology
  • Neutrophils / metabolism*
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Shear Strength*
  • Signal Transduction*
  • p21-Activated Kinases / metabolism*
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Actin Depolymerizing Factors
  • RAC1 protein, human
  • Proto-Oncogene Proteins c-abl
  • LIMK1 protein, human
  • Lim Kinases
  • PAK1 protein, human
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein