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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Collagen Type III / pharmacology*
  • Conserved Sequence
  • Enzyme Activation / drug effects
  • Evolution, Molecular
  • HEK293 Cells
  • Humans
  • Ligands
  • Malformations of Cortical Development / genetics
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Structure, Secondary
  • Protein Transport / drug effects
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects
  • rhoA GTP-Binding Protein / metabolism*


  • Collagen Type III
  • GPR56 protein, mouse
  • Ligands
  • Receptors, G-Protein-Coupled
  • rhoA GTP-Binding Protein

Supplementary concepts

  • Polymicrogyria, Bilateral Frontoparietal