Luo Rong, Jeong Sung-Jin, Yang Annie, Wen Miaoyun, Saslowsky David E, Lencer Wayne I, Araç Demet, Piao Xianhua
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Division of Gastroenterology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2014 Jun 20;9(6):e100043. doi: 10.1371/journal.pone.0100043. eCollection 2014.
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.
GPR56是粘附性G蛋白偶联受体（GPCR）家族的成员。尽管GPR56在大脑发育中很重要，其突变会导致一种名为双侧额顶叶多小脑回（BFPP）的严重人类脑畸形，但信号传导机制在很大程度上仍不清楚。与许多其他粘附性GPCR一样，GPR56通过GPCR自蛋白水解诱导（GAIN）结构域裂解为N端和C端片段（GPR56N和GPR56C）；然而，这种裂解的生物学意义尚不清楚。利用最近鉴定出的GPR56配体以及BFPP相关突变的存在，我们研究了GPR56信号传导的分子机制。我们证明配体结合使GPR56N从膜结合的GPR56C释放，并触发GPR56C与脂筏的结合以及RhoA激活。此外，BFPP相关突变之一L640R不影响胶原蛋白III诱导的GPR56与脂筏的结合。相反，它特异性地消除了胶原蛋白III介导的RhoA激活。总之，这些发现揭示了一种可能适用于粘附性GPCR家族其他成员的新信号传导机制。
