title: Transcriptional induction of salt-inducible kinase 1 by transforming growth factor β leads to negative regulation of type I receptor signaling in cooperation with the Smurf2 ubiquitin ligase.
abstract: Transforming growth factor β (TGFβ) regulates many physiological processes and requires control mechanisms to safeguard proper and timely action. We have previously described how negative regulation of TGFβ signaling is controlled by the serine/threonine kinase salt-inducible kinase 1 (SIK1). SIK1 forms complexes with the TGFβ type I receptor and with the inhibitory Smad7 and down-regulates the type I receptor. We now demonstrate that TGFβ induces SIK1 levels via a direct transcriptional mechanism that implicates the Smad proteins, and we have mapped a putative enhancer element on the SIK1 gene. We provide evidence that the ubiquitin ligase Smurf2 forms complexes and functionally cooperates with SIK1. Both the kinase activity of SIK1 and the ubiquitin ligase activity of Smurf2 are important for proper type I receptor turnover. We also show that knockdown of endogenous SIK1 and Smurf2 enhances physiological signaling by TGFβ that leads to epithelial growth arrest. In conclusion, TGFβ induces expression of Smad7, Smurf2, and SIK1, the products of which physically and functionally interlink to control the activity of this pathway.
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala University, SE-751 24 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönn
authors.forename: Michael
authors.initials: M
authors.lastname: Vanlandewijck
authors.forename: Erna
authors.initials: E
authors.lastname: Raja
authors.forename: Marcin
authors.initials: M
authors.lastname: Kowanetz
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kowanetz
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Vasilaki
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Aristidis
authors.initials: A
authors.lastname: Moustakas
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D019556:COS Cells; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008907:Mink; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; D000077293:Receptor, Transforming Growth Factor-beta Type I