Control of TGFβ signaling by degradation of Smads, TGFβ signal transducers

通过降解 Smads、TGFβ 信号转导器来控制 TGFβ 信号传导

• 批准号: 13672294
• 负责人: HAYASHI Hidetoshi
• 金额: $ 2.3万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672294/
• 关键词: TGFβ; Smad; Smurf; E3 ligase; proteasome; ubiquitination; acetylation; TGFbeta; proteasome; ubiquitin; phosphorylation; smad3; ユビキチンリカーゼ; タンパク分解; smurf; Roc1

Smad proteins are crucial molecules for the intracellular signaling of transforming growth factor-β (TGF-β). Upon receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate transcription of a select set of target genes. Here we investigated the turnover of Smad3, positively regulating Smad for TGF-β signaling. In the steady state, proteasome inhibition leads to the stabilization of Smad3 protein. Smad proteins are multi-ubiquitinated and degraded independently of its phosophorylation induced by the TGF-β receptors. Moreover, the degradation of Smad3 was enhanced by the treatment with TGF-β, and phosphorylated Smad3 was accumulated by proteasome inhibition. In addition, ubiquitination of phosphorylated Smad3 but not SmadS (3SA), a receptor-mediated phosphorylation incompetent mutant, was observed in the nucleus after treatment with TGF-β. These studies suggest that at steady state Smad3 is constitutively degraded through ubiquitin proteasome pathway in the cytoplasm and that in response to TGF-β it is phosphorylated and translocates into nuclei, where it is degraded through ubiquitin proteasome pathway.

Smad 蛋白是转化生长因子-β (TGF-β) 细胞内信号转导的关键分子，在受体诱导激活后，Smad 蛋白被磷酸化并转移到细胞核，以激活一组选定的靶基因的转录。 Smad3 的更新，正向调节 Smad 的 TGF-β 信号转导 在稳定状态下，蛋白酶体抑制导致 Smad3 蛋白被多泛素化并独立于其降解。此外，TGF-β 处理增强了 Smad3 的降解，并且磷酸化的 Smad3 通过蛋白酶体抑制而积累。此外，磷酸化的 Smad3 泛素化，但受体 SmadS (3SA) 没有泛素化。在用 TGF-β 处理后，在细胞核中观察到 Smad3 介导的磷酸化无能突变体。通过细胞质中的泛素蛋白酶体途径组成型降解，并且响应 TGF-β，它被磷酸化并易位到细胞核中，在细胞核中通过泛素蛋白酶体途径降解。

项目成果

T.Matsumura et al.: "TGFβ down-regulates IL-1-induced functional TLR2 expression in murine hepatocytes"Immunology. (in press). (2003)

T. Matsumura 等人：“TGFβ 下调小鼠肝细胞中 IL-1 诱导的功能性 TLR2 表达”《免疫学》（出版中）。

T. Matsumura et al.: "TGFβ down-regulates IL-1-induced functional TLR2 expression in murine hepatocytes"Immunology. (in press). (2003)

T. Matsumura 等人：“TGFβ 下调小鼠肝细胞中 IL-1 诱导的功能性 TLR2 表达”《免疫学》（出版中）。

T.Matsumura, T.Degawa, T.Takii, H.Hayashi, et al.: "TRAF6-NF-κB pathway is essential for IL-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes"Immunology. (in press). (2003)

T.Matsumura、T.Dekawa、T.Takii、H.Hayashi 等人：“TRAF6-NF-κB 通路对于小鼠肝细胞中 IL-1 诱导的 TLR2 表达及其对 TLR2 配体的功能反应至关重要”。 （正在出版）（2003）。

T. Hattori et al.: "C/EBP family transcription factors are degraded by the proteasome but stabilized by forming dimer"Oncogene. 22(9). 1273-1280 (2003)

T. Hattori 等人：“C/EBP 家族转录因子被蛋白酶体降解，但通过形成二聚体而稳定”癌基因。

T.Hattori et al.: "C/EBP family transcription factors are degraded by the proteasome but stabilized by forming dimer"Oncogene. 22(9). 1273-1280 (2003)

T.Hattori 等人：“C/EBP 家族转录因子被蛋白酶体降解，但通过形成二聚体而稳定”癌基因。