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Updated: Dec 30, 2025

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Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses

Luke D Hutchinson1,2, Nicola J Darling1, Stephanos Nicolaou3,4

  • 1MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Sir James Black Centre, Dow Street, Dundee, DD1 5EH, UK.

Cell Death & Disease
|January 24, 2020
PubMed

Insights

Small molecule inhibitors of salt-inducible kinases (SIKs) were found to regulate transforming growth factor-beta (TGFβ) signaling. SIK inhibition attenuated TGFβ-mediated transcription and potentiated apoptosis, revealing a novel role for SIKs in TGFβ responses.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGFβ) signaling pathways regulate critical cellular processes like proliferation, differentiation, epithelial-mesenchymal transition (EMT), and apoptosis.
  • Strict regulation of TGFβ signaling is essential for context-dependent physiological responses.

Purpose of the Study:

  • To identify novel regulatory components of the TGFβ signaling pathway.
  • To investigate the role of salt-inducible kinases (SIKs) in TGFβ-mediated responses.

Main Methods:

  • A pharmacological screen using a cell line engineered to report TGFβ-responsive PAI-1 gene transcription.
  • Small molecule inhibitors targeting SIKs were employed.
  • Genetic inactivation of SIK isoforms was performed.
  • Assessment of receptor-mediated SMAD phosphorylation, complex formation, and nuclear translocation.

Main Results:

  • Small molecule inhibitors of SIKs attenuated TGFβ-mediated PAI-1 transcription without impacting SMAD pathway components upstream of nuclear translocation.
  • Genetic inactivation of SIK isoforms also reduced TGFβ-dependent transcriptional responses.
  • Pharmacological inhibition of SIKs potentiated TGFβ-induced apoptotic cell death.

Conclusions:

  • Salt-inducible kinases (SIKs) play a novel role in modulating TGFβ-mediated transcriptional responses.
  • SIKs are involved in regulating TGFβ-induced cellular processes, including apoptosis.

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