The type I TGF-β receptor is covalently modified and regulated by sumoylation

Post-translational sumoylation, the covalent attachment of a small ubiquitin-like modifier (SUMO), regulates the functions of proteins engaged in diverse processes. Often associated with nuclear and perinuclear proteins, such as transcription factors, it is not known whether SUMO can conjugate to cell surface receptors for growth factors to regulate their functions. We show that the type I TGF-β receptor, TβRI, is sumoylated in response to TGF-β and that its sumoylation requires the kinase activities of both TβRI and the type II TGF-β receptor, TβRII. Sumoylation of TβRI enhances receptor function by facilitating the recruitment and phosphorylation of Smad3, consequently regulating TGF-β-induced transcription and growth inhibition. TβRI sumoylation modulates dissemination of transformed cells in a mouse model of TβRI-stimulated metastasis. Hence, TβRI sumoylation controls TGF-β responsiveness, with implications for tumor progression. Sumoylation of cell surface receptors may regulate other growth factor responses.