GPR56 and TG2: Possible Roles in Suppression of Tumor Growth by the Microenvironment

Abstract

Metastasis is a complex process that involves multiple levels of cell-cell interaction. Among these interactions, tumor-stroma interactions are being actively investigated. Metastatic cells are hypothesized to show gene expression changes that contribute to their survival and growth at the distant site. Such changes could contribute either to enhancement of growth or to evasion of growth inhibition by the normal tissue environment thus allowing growth as metastases. Our recent report that tumors from highly metastatic melanoma derivatives express low levels of a suppressor of tumor progression, GPR56, is consistent with such a model. GPR56 associates in a complex with Gaq and the tetraspanin protein CD81. We further identified a ligand that interacts with GPR56 in the extracellular matrix (ECM) as TG2, a major crosslinking enzyme in the matrix. TG2 also binds to fibronectin and integrins and affects their cell adhesion functions. TG2 itself has been implicated in suppression of tumor progression; therefore TG2 might serve as a host defense against the invading metastatic cells. The highly metastatic cells may escape from this inhibition by down-regulation of GPR56. Much future work will be needed to test this hypothesis and further our understanding of metastasis in general.

Disease-associated GPR56 Mutations Cause Bilateral Frontoparietal Polymicrogyria via Multiple Mechanisms

“…Furthermore, it enables us to confirm unambiguously that human TG2 is not a cellular ligand for GPR56. This result not only points to the presence of a novel protein ligand for GPR56 but also challenges the biological relevance of the interaction between human GPR56 and mouse TG2 (20,27).…”

International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands

“…Collagen, type III, a-1 (gene symbol, COL3A1) has been proposed as the ligand of GPR56 (Luo et al, 2011), signaling by activating RhoA through coupling to G 12/13 . Transglutaminase 2, a major crosslinking enzyme in the extracellular matrix, has also been proposed as a ligand of GPR56 (Xu and Hynes, 2007).…”

Agonistic Antibodies Reveal the Function of GPR56 in Human Glioma U87-MG Cells

“…Therefore, research of this family has not progressed well. It has been reported that transglutaminase 2 (TG2), 6) CD81, 7) and collagen III 8) are the interactors of GPR56. Collagen III has been shown to inhibit the cell migration of neural progenitor cells.…”