Abstract LB-144: GPR56 internalizes and degrades TG2 in melanoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA 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. Our earlier study showed that an adhesion G protein-coupled receptor (GPCR), GPR56, inhibits melanoma growth and metastasis 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 generated immunodeficient Tg2-/- mice and performed xenograft transplantation studies in these mice. Our results revealed an antagonistic relationship between GPR56 and TG2 during melanoma growth: whereas TG2 promotes melanoma growth, GPR56 antagonizes this effect via receptor-mediated internalization and degradation. Furthermore, the down-regulation of TG2 by GPR56 is associated with a reduction in the levels of fibronectin and focal adhesion kinase (FAK), suggesting that the fibronectin-mediated cell adhesion is compromised upon GPR56 expression in melanoma. Taken together, our findings provide genetic evidence for the function of TG2 in GPR56-mediated melanoma inhibition. The uncovered antagonistic relationship between GPR56 and TG2 proposes a mechanism by which ECM accumulation/crosslinking may be reversed, and thus might be exploited for cancer control and treatment. Citation Format: Liquan Yang, Scott Friedland, Nancy Corson, Lei Xu. GPR56 internalizes and degrades TG2 in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-144. doi:10.1158/1538-7445.AM2014-LB-144