2. Academic Validation
  3. Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses

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

  • Cell Death Dis. 2020 Jan 22;11(1):49. doi: 10.1038/s41419-020-2241-6.
Luke D Hutchinson 1 2,  Nicola J Darling 1,  Stephanos Nicolaou 3 4,  Ilaria Gori 3,  Daniel R Squair 1,  Philip Cohen 1,  Caroline S Hill 3,  Gopal P Sapkota 5
Affiliations

Affiliations

  • 1 MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Sir James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
  • 2 Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
  • 3 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 4 The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK.
  • 5 MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Sir James Black Centre, Dow Street, Dundee, DD1 5EH, UK. [email protected].
PMID: 31969556 DOI: 10.1038/s41419-020-2241-6
Abstract

The signalling pathways initiated by members of the Transforming Growth Factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT) and Apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen by using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1. The screen revealed that small molecule inhibitors of salt-inducible kinases (SIKs) attenuate TGFβ-mediated transcription of PAI-1 without affecting receptor-mediated SMAD phosphorylation, SMAD complex formation or nuclear translocation. We provide evidence that genetic inactivation of SIK isoforms also attenuates TGFβ-dependent transcriptional responses. Pharmacological inhibition of SIKs by using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGFβ stimulation. Our data therefore provide evidence for a novel function of SIKs in modulating TGFβ-mediated transcriptional and cellular responses.

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