title: Mechanism for adhesion G protein-coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation.
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.
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Luo
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Annie
authors.initials: A
authors.lastname: Yang
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Miaoyun
authors.initials: M
authors.lastname: Wen
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Saslowsky
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Demet
authors.initials: D
authors.lastname: Araç
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Piao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D024061:Collagen Type III / Q000494:pharmacology*; D017124:Conserved Sequence; D004789:Enzyme Activation / Q000187:drug effects; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D054220:Malformations of Cortical Development / Q000235:genetics; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D024061:Collagen Type III; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D020742:rhoA GTP-Binding Protein; C524781:Adgrg1 protein, mouse