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

Department of Cell and Tissue Biology, Program in Cell Biology, University of California - San Francisco, California 94143, USA.
Nature Cell Biology (Impact Factor: 20.06). 07/2008; 10(6):654-64. DOI: 10.1038/ncb1728
Source: PubMed

ABSTRACT 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. Here we show that the type I transforming growth factor-beta (TGF-beta) receptor, T beta RI, is sumoylated in response to TGF-beta and that its sumoylation requires the kinase activities of both T beta RI and the type II TGF-beta receptor, T beta RII. Sumoylation of T beta RI enhances receptor function by facilitating the recruitment and phosphorylation of Smad3, consequently regulating TGF-beta-induced transcription and growth inhibition. T beta RI sumoylation modulates the dissemination of transformed cells in a mouse model of T beta RI-stimulated metastasis. T beta RI sumoylation therefore controls responsiveness to TGF-beta, with implications for tumour progression. Sumoylation of cell-surface receptors may regulate other growth factor responses.

Download full-text


Available from: Rosemary J Akhurst, Aug 23, 2015
  • Source
    • "Sumoylation can play both positive and negative roles in the TGFb pathway. In the case of TbRI, sumoylation stabilizes Smad2/3 binding to the TbRI receptor, leading to enhanced Smad activation (Kang et al., 2008). Sumoylation of Smad3 stimulates its nuclear export and inhibits Smad-dependent transcription (Imoto et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: TIF1γ, a new actor of TGFβ signaling, inhibits the Smad4-mediated TGFβ response by interaction with Smad2/3 or ubiquitination of Smad4. We have shown that TIF1γ participates in TGFβ signaling as a negative regulator of Smad4 during the TGFβ-induced epithelial-to-mesenchymal transition in mammary epithelial cells and during terminal differentiation of mammary alveolar epithelial cells and lactation. We demonstrate here that TIF1γ is sumoylated and interacts with Ubc9, the only known SUMO-conjugating enzyme. Four functional sumoylation sites lie within the middle domain of TIF1γ, the Smad interaction domain. We show that a sumoylation-defective TIF1γ mutant significantly reduces TIF1γ inhibition of Smad complexes and that of the Smad-mediated TGFβ transcriptional response. Moreover, chromatin immunoprecipitation experiments indicate that TIF1γ sumoylation is required to limit Smad4 binding on the PAI-1 TGFβ target gene promoter. Ectopic expression of TIF1γ in mammary epithelial cells inhibits TGFβ-induced EMT, an effect relieved by expression of non-sumoylated TIF1γ. Taken together, our results identify a new TGFβ regulatory layer, whereby sumoylation strengthens the TIF1γ repressive action on canonical TGFβ signaling.
    Journal of Cell Science 06/2013; 126(16). DOI:10.1242/jcs.126748 · 5.33 Impact Factor
  • Source
    • "Protein posttranslational modifications are important for fine-tuning the control of TGF-b receptor function (Feng and Derynck, 2005; Kang et al., 2009; Moustakas and Heldin, 2009; Wrighton et al., 2009). For instance, TbRI could undergo ubiquitination and sumoylation, processes that mediate receptor degradation and activation, respectively (Kang et al., 2008; Lö nn et al., 2009). Ubiquitination has also been suggested to regulate TbRII stability (Atfi et al., 2007), although the ubiquitin E3 ligase for TbRII is still unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor β (TGF-β) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-β signaling is associated with the development of many cancers, including leukemia, though the molecular mechanisms are largely unclear. Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-β signaling by neddylating and stabilizing the type II receptor (TβRII). Knockout of c-Cbl decreases the TβRII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-β stimulation, while c-Cbl overexpression stabilizes TβRII and sensitizes leukemia cells to TGF-β. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to TβRII at Lys556 and Lys567. Neddylation of TβRII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting TβRII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant TβRII neddylation and leukemia development.
    Molecular cell 02/2013; 749(3). DOI:10.1016/j.molcel.2012.12.002 · 14.46 Impact Factor
  • Source
    • "This site lies close to the SUMOylated lysine (K389) and SUMOylation levels of the S387Y mutant were significantly decreased. Indeed, similar to the non-SUMOylatable mutant, TGF-β-mediated Smad3 activation was also reduced in this mutant (Kang et al., 2008). Together, these results suggest that the S387Y mutant potentially enhances metastasis by mediating downregulation of TGF-β signalling through inhibition of TβRI SUMOylation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The post-translational modification of proteins is critical for the spatial and temporal regulation of signalling cascades. This is especially important in the CNS where the processes affecting differentiation, growth, targeting and communication between neurones are highly complex and very tightly regulated. In recent years it has emerged that modification of proteins by members of the SUMO (small ubiquitin-related modifier) family of proteins play key roles in neuronal function. SUMOylation involves the covalent conjugation of a member of the SUMO family to lysine residues in target proteins. Multiple nuclear and perinuclear SUMOylation targets have been reported to be involved in nuclear organisation and transcriptional regulation. In addition, a growing number of extranuclear SUMO substrates have been identified that can have important acute effects on neuronal function. The SUMOylation of both intra- and extranuclear proteins have been implicated in a diverse array of processes that have far-reaching implications for neuronal function and pathophysiology. Here we review the current understanding of the targets and consequences of protein SUMOylation in the brain and examine its established and potential involvement in a wide range of neurological and neurodegenerative diseases.
    Brain Research Reviews 04/2010; 64(1):195-212. DOI:10.1016/j.brainresrev.2010.04.002 · 5.93 Impact Factor
Show more