The multiple roles of salt-inducible kinases in regulating physiology.

Salt-Inducible kinases, which comprise a family of three homologous serine-threonine kinases were first described for their role in sodium sensing, but have since been shown to regulate multiple aspects of physiology. These kinases are activated or deactivated in response to extracellular signals that are cell surface receptor mediated, and go on to phosphorylate multiple targets including the transcription co-factors CRTC1-3 and the Class IIa histone deacetylases (HDACs). Thus, the SIK family conveys signals about the cellular environment to reprogram transcriptional and post-transcriptional processes in response. In this manner, SIKs have been shown to regulate metabolic responses to feeding/fasting, cell division and oncogenesis, inflammation, and immune responses and most recently, sleep and circadian rhythms. Sleep and circadian rhythms are master regulators of physiology and are exquisitely sensitive to regulation by environmental light, and physiological signals such as need for sleep. Salt-Inducible kinases have been shown to be central the molecular control of both these processes. Here we summarise the molecular mechanisms by which SIKs control these different domains of physiology and highlight where there is mechanistic overlap with sleep/circadian rhythm control.