Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 417, Issue C, Pages 36-51Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2015.09.002
Keywords
Chemerin; signaling; CMKLR1; GPR1; RhoA; SRF; Chemotaxis
Categories
Funding
- Canadian Institutes of Health Research
- Izaak Walton Killam Predoctoral Scholarship
- Canadian Institutes of Health Research Canada Graduate Scholarship
- Nova Scotia Health Research Foundation Masters Student Research Award
- National Sciences and Engineering Research Council of Canada (NSERC)
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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, G alpha(i/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, G alpha(i/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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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