Luo, RongJeong, Sung-JinYang, AnnieWen, MiaoyunSaslowsky, David E.Lencer, Wayne I.Araç, DemetPiao, Xianhua2014-07-072014Luo, Rong, Sung-Jin Jeong, Annie Yang, Miaoyun Wen, David E. Saslowsky, Wayne I. Lencer, Demet Araç, and Xianhua Piao. 2014. “Mechanism for Adhesion G Protein-Coupled Receptor GPR56-Mediated RhoA Activation Induced By Collagen III Stimulation.” PLoS ONE 9 (6): e100043. doi:10.1371/journal.pone.0100043. http://dx.doi.org/10.1371/journal.pone.0100043.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406730GPR56 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.en-USBiology and Life SciencesCell BiologySignal TransductionCell SignalingMolecular BiologyNeuroscienceMolecular NeuroscienceJournal Article2014-07-0710.1371/journal.pone.0100043