Biochemical and biophysical properties of extracellular matrix (ECM) regulate multiple aspects of cancer cell behavior during tumor progression. The mechanisms of these regulations are not well defined. We previously reported that an atypical G protein-coupled receptor (GPCR), GPR56, inhibited melanoma growth and metastasis and its N-terminus binds to tissue transglutaminase, TG2, a major cross-linking enzyme in ECM. We thus postulated that GPR56 might suppress melanoma progression by influencing ECM properties through its interaction with TG2. To test this, we examined the effects of GPR56 on melanoma growth in the presence or absence of TG2, using the immunodeficient Tg2+/+ or Tg2−/ mice. Our results showed that the crosslinking enzyme, TG2, promoted melanoma growth, but this tumor-promoting effect was antagonized by GPR56. The mechanisms of this antagonism were revealed through a series of immunohistochemical and biochemical analyses. In GPR56-expressing cells, the extracellular TG2 was internalized by GPR56 and subsequently degraded in a lysome-dependent manner, resulting in a down-regulation of TG2 in ECM. This down-regulation of TG2 by GPR56 led to changes in the deposition of TG2 and other matrix proteins in melanomas and a reduction in melanoma growth. Taken together, we present evidence that a surface receptor on melanoma cells, GPR56, regulates the turnover of the crosslinking enzyme, TG2, in the tumor microenvironment, leading to changes in ECM deposition and melanoma progression.

Citation Format: Liquan Yang, Sonali Mohanty, Nancy Corson, Lei Xu. GPR56 regulates the turnover of tissue transglutaminase and tumor growth in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 210. doi:10.1158/1538-7445.AM2013-210

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.