Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses
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Luke D Hutchinson Nicola J Darling Stephanos Nicolaou Ilaria Gori Daniel R Squair Philip Cohen Caroline Hill Gopal P SapkotaAbstract
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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Journal Cell Death and Disease
Volume 11
Issue number 1
Pages 49
Available online
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Publisher website (DOI) 10.1038/s41419-020-2241-6
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Europe PubMed Central 31969556
Pubmed 31969556
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