TGFbeta induces SIK to negatively regulate type I receptor kinase signaling.

The Journal of cell biology (2008-08-30)
Marcin Kowanetz, Peter Lönn, Michael Vanlandewijck, Katarzyna Kowanetz, Carl-Henrik Heldin, Aristidis Moustakas
RESUMEN

Signal 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.

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Monoclonal Anti-β-Tubulin I+II antibody produced in mouse, clone JDR.3B8, ascites fluid

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