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bioRxiv · 10.1101/809228

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

Hutchinson, L. D.·Darling, N. J.·Nicolaou, S.·Gori, I.·Squair, D. R.·Cohen, P.·Hill, C. S.·Sapkota, G. P.
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Abstract

AbstractThe signalling pathways initiated by members of the transforming growth factor-{beta} (TGF{beta}) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT), and apoptosis. TGF{beta} signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGF{beta} signalling pathway, we performed a pharmacological screen using a cell line engineered to report the endogenous transcription of the TGF{beta}-responsive target gene PAI-1. The screen revealed that small-molecular inhibitors of salt-inducible kinases (SIKs) attenuate TGF{beta}-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 TGF{beta}-dependent transcriptional responses. Pharmacological inhibition of SIKs using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGF{beta} stimulation. Our data therefore provides evidence for a novel function of SIKs in modulating TGF{beta}-mediated transcriptional and cellular responses.

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Hutchinson, L. D., Darling, N. J., Nicolaou, S., Gori, I., Squair, D. R., Cohen, P., Hill, C. S., Sapkota, G. P.. 2019-10-17. Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses. https://doi.org/10.1101/809228

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