title: CMKLR1 and GPR1 mediate chemerin signaling through the RhoA/ROCK pathway.
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.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Rourke
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Dranse
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. Electronic address: csinal@dal.ca.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sinal
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D019707:Receptors, Chemokine / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C102741:CMKLR1 protein, human; D018925:Chemokines; C504821:GPR1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C476858:SRF protein, human; D026362:Serum Response Factor; C066737:RHOA protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: CMKLR1; Chemerin signaling; Chemotaxis; GPR1; RhoA; SRF