TGFbeta induces SIK to negatively regulate type I receptor kinase signaling.
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.
Kowanetz
Marcin
M
Ludwig Institute for Cancer Research, Uppsala University, Box 595 Biomedical Center, Uppsala, Sweden.
Lönn
Peter
P
Vanlandewijck
Michael
M
Kowanetz
Katarzyna
K
Heldin
Carl-Henrik
CH
Moustakas
Aristidis
A
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human