TGFβ induces SIK to negatively regulate type I receptor kinase signaling
2008 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 182, no 4, 655-662 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
The Rockefeller University Press , 2008. Vol. 182, no 4, 655-662 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-103239DOI: 10.1083/jcb.200804107ISI: 000259050000007PubMedID: 18725536OAI: oai:DiVA.org:uu-103239DiVA: diva2:217768