Activation of myeloid cell-specific adhesion class G protein-coupled receptor EMR2 via ligation-induced translocation and interaction of receptor subunits in lipid raft microdomains.
The adhesion class G protein-coupled receptors (adhesion-GPCRs) play important roles in diverse biological processes ranging from immunoregulation to tissue polarity, angiogenesis, and brain development. These receptors are uniquely modified by self-catalytic cleavage at a highly conserved GPCR proteolysis site (GPS) dissecting the receptor into an extracellular subunit (α) and a seven-pass transmembrane subunit (β) with cellular adhesion and signaling functions, respectively. Using the myeloid cell-restricted EMR2 receptor as a paradigm, we exam the mechanistic relevance of the subunit interaction and demonstrate a critical role for GPS autoproteolysis in mediating receptor signaling and cell activation. Interestingly, two distinct receptor complexes are identified as a result of GPS proteolysis: one consisting of a noncovalent α-β heterodimer and the other comprising two completely independent receptor subunits which distribute differentially in membrane raft microdomains. Finally, we show that receptor ligation induces subunit translocation and colocalization within lipid rafts, leading to receptor signaling and inflammatory cytokine production by macrophages. Our present data resolve earlier conflicting results and provide a new mechanism of receptor signaling, as well as providing a paradigm for signal transduction within the adhesion-GPCR family.
Graduate Institute of Biomedical Sciencesa, College of Medicine,b Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.
Yi-Shu
YS
Huang
Nien-Yi
NY
Chiang
Ching-Hsun
CH
Hu
Cheng-Chih
CC
Hsiao
Kai-Fong
KF
Cheng
Wen-Pin
WP
Tsai
Simon
S
Yona
Martin
M
Stacey
Siamon
S
Gordon
Gin-Wen
GW
Chang
Hsi-Hsien
HH
Lin
D002478:Cells, Cultured; D002633:Chemotaxis; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000378:metabolism / Q000648:ultrastructure; D021962:Membrane Microdomains / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
C412456:ADGRE2 protein, human; D008024:Ligands; D021122:Protein Subunits; D043562:Receptors, G-Protein-Coupled