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- W2334026053 abstract "Signal transduction pathways, like transforming growth factor beta (TGFβ), regulate many physiological processes and require control mechanisms to safeguard proper and timely action. Dysregulation of TGFβ signaling is established as a major player in cancer progression. We have recently described how negative regulation of TGFβ signaling is controlled by the serine/threonine kinase salt-inducible kinase (SIK). SIK is induced by TGFβ and forms protein complexes with the TGFβ type I receptor and with the inhibitory Smad7, which leads to type I receptor downregulation. We now investigate this mechanism further and demonstrate similarities between TGFβ/Smad-mediated immediate-early induction of SIK and Smad7. We also relate another protein of the negative feedback loop of TGFβ signaling, the E3 ubiquitin ligase Smurf2, to this mechanism of regulation. We provide evidence that Smurf2 cooperates with SIK to downregulate the type I receptor. Both the kinase activity of SIK and the ubiquitin ligase activity of Smurf2 are important for proper receptor turnover. However, Smurf2 does not directly bind to SIK, but participates in the complex via the PY-motif of Smad7. We thus establish a central role for Smad7 during SIK-mediated receptor downregulation. Finally, we explore the role of SIK in a cancer context by investigating its expression profile in human prostate cancer tissues. In conclusion, we have uncovered a phosphorylation/ubiquitination-dependent mechanism for TGFβ receptor downregulation that could play important roles during cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1982. doi:10.1158/1538-7445.AM2011-1982" @default.
- W2334026053 created "2016-06-24" @default.
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- W2334026053 date "2011-04-15" @default.
- W2334026053 modified "2023-10-17" @default.
- W2334026053 title "Abstract 1982: TGF-beta induced SIK cooperates with Smurf2 to negatively regulate type I receptor kinase signaling" @default.
- W2334026053 doi "https://doi.org/10.1158/1538-7445.am2011-1982" @default.
- W2334026053 hasPublicationYear "2011" @default.
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