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: 19.68). 07/2008; 10(6):654-64. DOI: 10.1038/ncb1728
Source: PubMed


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.

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    • "Recent evidences suggest that SUMOylation regulates the TGFb signaling pathway. SUMO modification significantly impacts on TGFb type I receptor (Kang et al., 2008), and Smad proteins function (Imoto et al., 2003; Lee et al., 2003; Lin et al., 2003; Liang et al., 2004). Moreover, TGFb directly impinge on Smad4 SUMOylation, through the stabilization of its E3 SUMO-ligase PIASxb (Ohshima and Shimotohno, 2003). "
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    ABSTRACT: Exposure of normal and tumor-derived cells to TGFβ results in different outcomes, depending on the regulation of key targets. The CDK inhibitor p27(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle arrest. TGFβ treatment inhibits p27(Kip1) degradation and induces its nuclear translocation, through mechanisms that are still unknown. Recent evidences suggest that SUMOylation, a post-translational modification able to modulate the stability and subcellular localization of target proteins, critically modifies members of the TGFβ signaling pathway. Here, we demonstrate that p27(Kip1) is SUMOylated in response to TGFβ treatment. Using different p27(Kip1) point mutants, we identified lysine 134 (K134) as the residue modified by small ubiquitin-like modifier 1 (SUMO1) in response to TGFβ treatment. TGFβ-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27(Kip1). We observed that SUMOylation regulated p27(Kip1) binding to CDK2, thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187. Importantly, p27(Kip1) SUMOylation was necessary for proper cell cycle exit following TGFβ treatment. These data indicate that SUMOylation is a novel regulatory mechanism that modulates p27(Kip1) function in response to TGFβ stimulation. Given the involvement of TGFβ signaling in cancer cell proliferation and invasion, our data may shed light on an important aspect of this pathway during tumor progression.
    Journal of Molecular Cell Biology 10/2015; DOI:10.1093/jmcb/mjv056 · 6.77 Impact Factor
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    • "Sumoylation changes the activity, subcellular localization, or stability of these proteins to influence signal transduction [15]. Sumoylation has been demonstrated to regulate the canonical TGF-β/Smad pathway through TβRI, Smad3, and Smad4 [10, 11, 38]. Several studies have shown that Smad4 is sumoylated by SUMO1 or SUMO2/3. "
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    ABSTRACT: Recent studies have shown that sumoylation is a posttranslational modification involved in regulation of the transforming growth factor- β (TGF- β ) signaling pathway, which plays a critical role in renal fibrosis in diabetic nephropathy (DN). However, the role of sumoylation in the regulation of TGF- β signaling in DN is still unclear. In the present study, we investigated the expression of SUMO (SUMO1 and SUMO2/3) and Smad4 and the interaction between SUMO and Smad4 in cultured rat mesangial cells induced by high glucose. We found that SUMO1 and SUMO2/3 expression was significantly increased in the high glucose groups compared to the normal group (P < 0.05). Smad4 and fibronectin (FN) levels were also increased in the high glucose groups in a dose-dependent manner. Coimmunoprecipitation and confocal laser scanning revealed that Smad4 interacted and colocalized with SUMO2/3, but not with SUMO1 in mesangial cells. Sumoylation (SUMO2/3) of Smad4 under high glucose condition was strongly enhanced compared to normal control (P < 0.05). These results suggest that high glucose may activate TGF- β /Smad signaling through sumoylation of Samd4 by SUMO2/3 in mesangial cells.
    BioMed Research International 05/2014; 2014:782625. DOI:10.1155/2014/782625 · 3.17 Impact Factor
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    • "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). "
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    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 · 5.43 Impact Factor
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