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

The 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 by using a cell line engineered to report the endogenous transcription of the TGF beta-responsive target gene PAI-1. The screen revealed that small molecule 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 by using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGF beta stimulation. Our data therefore provide evidence for a novel function of SIKs in modulating TGF beta-mediated transcriptional and cellular responses.