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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.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Apr 13; Vol. 287 (16), pp. 12867-78. Date of Electronic Publication: 2012 Feb 29. - Publication Year :
- 2012
-
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.
- Subjects :
- Animals
Breast Neoplasms
COS Cells
Cell Line, Transformed
Chlorocebus aethiops
Down-Regulation physiology
Female
Gene Expression Regulation, Neoplastic physiology
HEK293 Cells
Humans
Keratinocytes cytology
Mink
Protein Serine-Threonine Kinases metabolism
RNA, Small Interfering genetics
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta metabolism
Respiratory Mucosa cytology
Smad7 Protein genetics
Smad7 Protein metabolism
Protein Serine-Threonine Kinases genetics
Transcriptional Activation physiology
Transforming Growth Factor beta metabolism
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22378783
- Full Text :
- https://doi.org/10.1074/jbc.M111.307249