GPR56/ADGRG1 Activation Promotes Melanoma Cell Migration via NTF Dissociation and CTF-Mediated Gα12/13/RhoA Signaling.
GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα12/13/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.
Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.
Nien-Yi
NY
Chiang
Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
Yen-Ming
YM
Peng
Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Urology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.
Horng-Heng
HH
Juang
Department of Anatomic Pathology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.
Tse-Ching
TC
Chen
Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
Hsiao-Lin
HL
Pan
Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.
Gin-Wen
GW
Chang
Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Anatomic Pathology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan. Electronic address: hhlin@mail.cgu.edu.tw.
Hsi-Hsien
HH
Lin
D045744:Cell Line, Tumor; D002465:Cell Movement; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D000072417:Protein Domains; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism; D060225:Tetraspanin 28 / Q000378:metabolism; D060245:Tetraspanin 29 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
C118925:ADGRG1 protein, human; C554798:CD81 protein, human; C554869:CD9 protein, human; D043562:Receptors, G-Protein-Coupled; D060225:Tetraspanin 28; D060245:Tetraspanin 29; C066737:RHOA protein, human; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein