GPR56 Inhibits Melanoma Growth by Internalizing and Degrading Its Ligand TG2

Abstract

Excessive accumulation of extracellular matrix (ECM) is a hallmark of tumor microenvironment and plays active roles during tumor progression. How this process is regulated and whether it is reversible for cancer treatment are outstanding questions. The adhesion G protein-coupled receptor GPR56 inhibits melanoma growth and binds to tissue transglutaminase (TG2), a major cross-linking enzyme in ECM. To understand the function of TG2 in GPR56-mediated melanoma inhibition, we performed xenograft studies in immunodeficient Tg2−/− mice. Our results revealed an antagonistic relationship between GPR56 and TG2 in melanoma: while TG2 and its crosslinking activity promote melanoma growth, GPR56 antagonizes this effect by internalizing and degrading it. The negative regulation of TG2 by GPR56 associates with the decreased deposition of a major ECM protein, fibronectin, and impaired accumulation of focal adhesion kinase, indicating that the GPR56-TG2 interaction regulates ECM deposition and cell-ECM adhesion. Taken together, our findings establish the roles of TG2 in GPR56-mediated melanoma inhibition. The uncovered antagonistic relationship between GPR56 and TG2 proposes a mechanism by which ECM accumulation/crosslinking in tumors may be reversed, and thus could have therapeutic potential for cancer control and treatment.

The integrin–collagen connection – a glue for tissue repair?

“…More recently, ablation of GPR56 has pointed to a cell-autonomous function in oligodendrocyte development (Giera et al, 2015). GPR56 also binds to other ligands, including tissue transglutaminase 2 (Yang et al, 2014).…”

Stachel -independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

“…For example, the aGPCR GPR56/ADGRG1 is involved in cortex development, oligodendrocyte development, muscle cell development, innate immunity, and cancer progression (11)(12)(13)(14)(15)(16)(17). Recent studies have highlighted the role of GPR56 in promoting progression of acute myeloid leukemia (18) and progastrin-dependent colon cancer (19) and suggested that a GPR56 inhibitor would be clinically desirable.…”

Insights into Transglutaminase 2 Function Gained from Genetically Modified Animal Models

“…Metastasis to lung and other organs was increased, although the individual metastasis size was smaller in TG2 À/À relative to wild-type mice ). TG2 was shown to interact in the extracellular matrix with the extracellular domain of the adhesion G protein-coupled receptor, GPR56 (Xu et al 2006;Yang et al 2014), which is a suppressor of melanoma tumor growth and metastasis, and which is markedly downregulated in highly metastatic cells. Xenograft studies in TG2 À/À mice [(De Laurenzi and Melino 2001), no reference to strain background] bred into immunodeficient Rag2 À/À mice (no reference to source or strain background) indicated that TG2 and its crosslinking activity promote melanoma growth (Yang et al 2014).…”

“…TG2 was shown to interact in the extracellular matrix with the extracellular domain of the adhesion G protein-coupled receptor, GPR56 (Xu et al 2006;Yang et al 2014), which is a suppressor of melanoma tumor growth and metastasis, and which is markedly downregulated in highly metastatic cells. Xenograft studies in TG2 À/À mice [(De Laurenzi and Melino 2001), no reference to strain background] bred into immunodeficient Rag2 À/À mice (no reference to source or strain background) indicated that TG2 and its crosslinking activity promote melanoma growth (Yang et al 2014). GPR56 inhibition of melanoma progression involves binding of the N-terminus of GPR56 to its ligand, TG2, in the melanoma extracellular matrix, followed by internalization and degradation of TG2 (Yang et al 2014).…”