TGFbeta induces SIK to negatively regulate type I receptor kinase signaling

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Updated: Jul 2, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

Marcin Kowanetz1, Peter Lönn, Michael Vanlandewijck

  • 1Ludwig Institute for Cancer Research, Uppsala University, Box 595 Biomedical Center, Uppsala, Sweden.

The Journal of Cell Biology
|August 30, 2008
PubMed

Insights

Salt-inducible kinase (SIK) negatively regulates transforming growth factor beta (TGFbeta) signaling by targeting ALK5 receptors for degradation. Loss of SIK enhances TGFbeta-mediated fibrotic and cytostatic gene responses.

Area of Science:

  • Cellular biology
  • Molecular signaling

Background:

  • Transforming growth factor beta (TGFbeta) signaling regulates diverse cellular functions through receptor kinases and Smad proteins.
  • Negative feedback mechanisms are crucial for controlling the duration and intensity of TGFbeta signaling.
  • Salt-inducible kinase (SIK) is an inducible gene target of TGFbeta/Smad signaling.

Purpose of the Study:

  • To investigate the role of SIK as a negative regulator in TGFbeta signaling.
  • To elucidate the mechanism by which SIK modulates TGFbeta receptor activity.

Main Methods:

  • Investigated the interaction between SIK, Smad7, and the TGFbeta type I receptor ALK5.
  • Assessed the requirement of SIK's kinase and ubiquitin-associated domains for ALK5 degradation.
  • Utilized gene knockout models to evaluate the impact of endogenous SIK loss on TGFbeta responses.

Main Results:

  • SIK forms a complex with Smad7 to down-regulate activated ALK5.
  • Both the kinase and ubiquitin-associated domain of SIK are essential for ALK5 degradation, with ubiquitin enhancing the process.
  • Loss of endogenous SIK leads to amplified fibrotic and cytostatic gene responses to TGFbeta.

Conclusions:

  • SIK acts as a critical negative regulator of TGFbeta signaling by promoting TGFbeta receptor turnover.
  • SIK's function is vital for maintaining physiological control over TGFbeta-mediated cellular processes, including fibrosis and cytostasis.

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