Phosphatidic acid regulates subcellular distribution of RA-GEFs critical for chemokine-dependent migration

Biochem Biophys Res Commun. 2020 Apr 2;524(2):325-331. doi: 10.1016/j.bbrc.2020.01.080. Epub 2020 Jan 26.

Abstract

Integrin activation by Rap1-GTP is pivotal for lymphocyte trafficking. In this study, we show the phosphatidic acid (PA)-dependent membrane distribution of RA-GEF-1 and -2 (also known as Rapgef2 and 6), which are guanine nucleotide exchange factors for Rap1, plays important roles in lymphocyte migration. RA-GEF-1 associates with PA through 919-967 aa within CDC25 homology domain, and the deletion of this region of RA-GEF-1 inhibits chemokine-dependent migration. Chemokine stimulation induces temporal production of PA on the plasma membrane, which is not necessary for Rap1 activation, but the translocation of RA-GEFs. Thus, chemokine-dependent generation of PA is critical for lymphocyte migration through membrane localization of RA-GEFs.

Keywords: Chemokine; Lymphocyte; Migration; Phosohatidic acid; RA-GEF; Rap1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement*
  • Chemokines / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • Mice
  • Phosphatidic Acids / metabolism*

Substances

  • CNrasGEF protein, mouse
  • Chemokines
  • Guanine Nucleotide Exchange Factors
  • Phosphatidic Acids