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lüll TGFbeta induces SIK to negatively regulate type I receptor kinase signaling Kowanetz M; Lonn P; Vanlandewijck M; Kowanetz K; Heldin CH; Moustakas AJ Cell Biol 2008[Aug]; 182 (4): 655-62Signal transduction by transforming growth factor beta (TGFbeta) coordinates physiological responses in diverse cell types. TGFbeta signals via type I and type II receptor serine/threonine kinases and intracellular Smad proteins that regulate transcription. Strength and duration of TGFbeta signaling is largely dependent on a negative-feedback program initiated during signal progression. We have identified an inducible gene target of TGFbeta/Smad signaling, the salt-inducible kinase (SIK), which negatively regulates signaling together with Smad7. SIK and Smad7 form a complex and cooperate to down-regulate the activated type I receptor ALK5. We further show that both the kinase and ubiquitin-associated domain of SIK are required for proper ALK5 degradation, with ubiquitin functioning to enhance SIK-mediated receptor degradation. Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFbeta. We thus identify in SIK a negative regulator that controls TGFbeta receptor turnover and physiological signaling.|Animals[MESH]|Cell Line[MESH]|Down-Regulation/*drug effects[MESH]|Enzyme Activation/drug effects[MESH]|Enzyme Induction/drug effects[MESH]|Humans[MESH]|Protein Binding/drug effects[MESH]|Protein Serine-Threonine Kinases/biosynthesis/chemistry/*metabolism[MESH]|Protein Structure, Tertiary[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/*metabolism[MESH]|Signal Transduction/*drug effects[MESH]|Smad7 Protein/metabolism[MESH]|Transforming Growth Factor beta/*pharmacology[MESH]|Ubiquitin/metabolism[MESH] |