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

Sep 13, 2015Molecular and cellular endocrinology

How CMKLR1 and GPR1 control chemerin signals through the RhoA/ROCK pathway

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Abstract

Chemerin activates the receptor GPR1, marking it as a functional receptor for the first time.

Chemerin engages in signaling through a pathway dependent on RhoA and ROCK to activate the transcription regulator serum-response factor (SRF).
Distinct species-specific and receptor-dependent variations are observed in the signaling and expression of SRF target genes EGR1, FOS, and VCL between GPR1 and CMKLR1.
Signaling pathways involving p38, Gαi/o, RhoA, and ROCK are necessary for the chemotaxis of L1.2 lymphocytes and AGS gastric adenocarcinoma cells in response to chemerin.
The findings suggest that both CMKLR1 and GPR1 utilize the RhoA/SRF signaling axis.

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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, 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.

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

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