A novel gain-of-function mutation of TGF-β receptor II promotes cancer progression via delayed receptor internalization in oral squamous cell carcinoma

We present a novel gain-of-function mutation of TGF-beta receptor II (T beta RII) found in human oral squamous cell carcinoma (OSCC). Expression of E221V/N238I mutant T beta RII enhanced TGF-beta signaling. Mutation of T beta RII conferred cells higher migratory and invasive capabilities and MMP-2 activity. In mouse tumor model, mutant tumors exhibited poor differentiation and E-cadherin relocalization to the cytosol. Lipid-raft-dependent endocytosis of T beta RII was attenuated in mutant T beta RII, suggesting that enhancement of TGF-beta signaling by this mutation is due to delayed T beta RII internalization. Taken together, our results show a novel gain-of-function T beta RII mutation, which enhances TGF-beta signaling leading to more invasive phenotypic changes in human OSCC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.