TY - GEN AB - <p>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 (GPR56<sup>N</sup> and GPR56<sup>C</sup>); 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 GPR56<sup>N</sup> from the membrane-bound GPR56<sup>C</sup> and triggers the association of GPR56<sup>C</sup> 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.</p> AD - Harvard University AD - Harvard University AD - Harvard University AD - Harvard University AD - Boston Children's Hospital AD - Boston Children's Hospital AD - University of Chicago AD - Harvard University AU - Luo, Rong AU - Jeong, Sung-Jin AU - Yang, Annie AU - Wen, Miaoyun AU - Saslowsky, David E. AU - Lencer, Wayne I. AU - Araç, Demet AU - Piao, Xianhua DA - 2014-06-20 ID - 8824 JF - PLOS ONE L1 - https://knowledge.uchicago.edu/record/8824/files/journal.pone.0100043.pdf L2 - https://knowledge.uchicago.edu/record/8824/files/journal.pone.0100043.pdf L4 - https://knowledge.uchicago.edu/record/8824/files/journal.pone.0100043.pdf LA - eng LK - https://knowledge.uchicago.edu/record/8824/files/journal.pone.0100043.pdf N2 - <p>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 (GPR56<sup>N</sup> and GPR56<sup>C</sup>); 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 GPR56<sup>N</sup> from the membrane-bound GPR56<sup>C</sup> and triggers the association of GPR56<sup>C</sup> 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.</p> PY - 2014-06-20 T1 - Mechanism for Adhesion G Protein-Coupled Receptor GPR56-Mediated RhoA Activation Induced By Collagen III Stimulation TI - Mechanism for Adhesion G Protein-Coupled Receptor GPR56-Mediated RhoA Activation Induced By Collagen III Stimulation UR - https://knowledge.uchicago.edu/record/8824/files/journal.pone.0100043.pdf Y1 - 2014-06-20 ER -