Effects of GPR56 on Melanoma Metastasis
GPR56 Promotes TG2 Endocytosis.
Melanoma is readily curable when it is at early stages, but becomes deadly once it metastasizes. We predicted that GPR56 inhibits melanoma metastasis via TG2-mediated ECM remodeling. To test this, we generated immunodeficient Tg2-/- mice and performed xenograft studies in these mice. Our results revealed that GPR56 inhibits melanoma growth by inducing the internalization and degradation of TG2 (see above figure). The down-regulation of TG2 by GPR56 associates with a reduction in fibronectin, a major ECM component and a binding partner of TG2, as well as focal adhesion kinase. These findings propose that ECM accumulation/crosslinking via TG2 could be reversed by GPR56 expression in melanomas and thus inducing ECM removal for cancer treatment is feasible. We will analyze how the endocytosis of GPR56 via TG2 is regulated, the signaling outcome of the ECM removal by GPR56, and its effects on melanoma metastasis. We will also extend these initial observations from xenograft tumor models to spontaneous melanoma model and examine the regulation of tumor ECM and cancer progression by the GPR56-TG2 pair in a more physiologically relevant context.
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