Sumoylating TGF-β Receptors

Abstract

Signaling by the transforming growth factor-β (TGF-β) superfamily is important in development and in adult tissues, and alterations in this pathway may contribute to some types of cancers and metastasis. Kang et al . provide evidence from in vitro experiments and from transfected cells that the type I subunit of the TGF-β receptor (TβRI) is modified by addition of the small molecule SUMO (see commentary by Miyazono et al .). Mutation analysis suggested that Lys 389 was the target for sumoylation. Phosphorylation of the TβRI, which is stimulated in response to ligand binding to the dimeric TβRI and TβRII complex, was necessary for SUMO modification because kinase-inactivated forms of a TβRI and TβRII chimera were not sumoylated in vitro or in transfected cells, and sumoylation was not detected in vitro if the reaction was carried out in the presence of a phosphatase. SUMO modification was detected most readily with an activated mutant of TβRI (caTβRI); moreover, in cells coexpressing caTβRI, SUMO-conjugating enzymes, tagged SUMO, and a mutant Smad3, the interaction between the receptor and Smad3 was enhanced (based on coimmunoprecipitation) compared to that in cells only expressing caTβRI and the mutant Smad3. Expression in Tgfbr1 – /– cells of a Lys 389 mutant TβRI that was not sumoylated resulted in less activation of Smads and less activation of TGF-β target genes (either endogenous targets or reporter genes) than did expression of the wild-type receptor, suggesting that sumoylation enhances TGF-β signaling. Ras-transformed mouse embryo fibroblasts from Tgfbr1 – /– animals showed decreased invasiveness in a cell migration assay and formed smaller and fewer metastatic tumor nodules when injected into mice when expressing the Lys 389 mutant TβRI than when expressing the wild-type receptor. Introduction of a mutation (Ser 387 Tyr) found in some human cancers resulted in a sumoylation-defective form of the receptor; however, in the tumor-metastasis model with Ras-transformed cells expressing this mutant form of the receptor, these cells formed fewer and smaller metastatic nodules than did cells expressing wild-type receptors. Thus, mechanisms by which TGF-β signaling contributes to cancer are complex. J. S. Kang, E. F. Saunier, R. J. Akhurst, R. Derynck, The type I TGF-β receptor is covalently modified and regulated by sumoylation. Nat. Cell Biol. 10 , 654-664 (2008). [PubMed] K. Miyazono, Y. Kamiya, K. Miyazawa, SUMO amplifies TGF-β signalling. Nat. Cell Biol. 10 , 635-637 (2008). [PubMed]