CMKLR1 and GPR1 mediate chemerin signaling through the RhoA/ROCK pathway

Mol Cell Endocrinol. 2015 Dec 5;417:36-51. doi: 10.1016/j.mce.2015.09.002. Epub 2015 Sep 9.

Abstract

Chemerin is an adipose-derived hormone that regulates immunity and energy homesotasis. To date, all known chemerin functions have been attributed to activation of the G protein-coupled receptor chemokine-like receptor-1 (CMKLR1). Chemerin is also the only known ligand for a second receptor, G protein-coupled receptor-1 (GPR1), whose signaling and function remains unknown. This study investigated the in vitro signal transduction mechanisms of CMKLR1 and GPR1 using a panel of luciferase-reporters and pathway-specific inhibitors. Herein we report the novel finding that chemerin signals through a RhoA and rho-associated protein kinase (ROCK)-dependent pathway for activation of the transcriptional regulator serum-response factor (SRF). Despite similarities in RhoA/ROCK, Gαi/o, and MAPK signaling, we also demonstrate species-specific and receptor-dependent variations in GPR1 and CMKLR1 signaling and expression of the SRF target genes EGR1, FOS and VCL. Moreover, we demonstrate that signaling through p38, Gαi/o, RhoA, and ROCK is required for chemerin-mediated chemotaxis of L1.2 lymphocytes and AGS gastric adenocarcinoma cells. These results provide, to our knowledge, the first empirical evidence that GPR1 is a functional chemerin receptor and identify RhoA/SRF as a novel chemerin-signaling axis via both CMKLR1 and GPR1.

Keywords: CMKLR1; Chemerin signaling; Chemotaxis; GPR1; RhoA; SRF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chemokines / metabolism*
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Receptors, Chemokine / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Serum Response Factor / metabolism
  • Signal Transduction
  • Species Specificity
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • CMKLR1 protein, human
  • Chemokines
  • GPR1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • RARRES2 protein, human
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • SRF protein, human
  • Serum Response Factor
  • RHOA protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein