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PLoS One. 2014 Jun 20;9(6):e100043. doi: 10.1371/journal.pone.0100043. eCollection 2014.

Mechanism for adhesion G protein-coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation.

Author information

1
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
2
Division of Gastroenterology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
3
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States of America.

Abstract

GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Despite the importance of GPR56 in brain development, where mutations cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), the signaling mechanism(s) remain largely unknown. Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); however, the biological significance of this cleavage is elusive. Taking advantage of the recent identification of a GPR56 ligand and the presence of BFPP-associated mutations, we investigated the molecular mechanism of GPR56 signaling. We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. Furthermore, one of the BFPP-associated mutations, L640R, does not affect collagen III-induced lipid raft association of GPR56. Instead, it specifically abolishes collagen III-mediated RhoA activation. Together, these findings reveal a novel signaling mechanism that may apply to other members of the adhesion GPCR family.

PMID:
24949629
PMCID:
PMC4065004
DOI:
10.1371/journal.pone.0100043
[Indexed for MEDLINE]
Free PMC Article

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