The multiple roles of salt-inducible kinases in regulating physiology

Abstract

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.

Multiple molecular links between the circadian clock and memory centers in honey bees

“…snap25, tutl). In addition, 3 of the genes peaking at 10:00 (Ap-1, SIK2, Inos) have been reported to function in modulating the core molecular clock in both insects and vertebrates (21)(22)(23). In the group of 31 NS DEGs with peak expression at 10:00, we found 12 genes functioning in neurotransmitter and biogenic amine signaling (e.g.…”

Inhibition of salt inducible kinases reduces rhythmic HIV-1 replication and reactivation from latency

“…At a molecular level, each cell has an intrinsic clock machinery, which is orchestrated by interlinked transcriptional/translational feedback loops [15]. Beyond the regulation through this core circadian machinery, other protein families have been identified that contribute to circadian regulation, among others salt inducible kinases (SIKs) which consist of three members: SIK1, SIK2, and SIK3 [16]. SIKs convey signals through phosphorylation of multiple targets, the best understood of which are class IIa histone deacetylases (HDACs) and cAMP-regulated transcriptional coactivators (CRTCs) [17,18].…”

The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity

“…Thus, SIK expression, activity, and cellular localization can change in response to numerous physiological signals. It is therefore not surprising that the SIK kinases have been shown to regulate a multitude of physiological functions as recently reviewed by Jagannath and Darling ( 1 , 2 ). Apart from being identified as key metabolic regulators, the SIK proteins have been shown to control bone formation and inflammation by modulating macrophage and mast cell function.…”

“…Although the three SIK isoforms share similar structures and targets, they play both distinct and redundant roles in regulating physiological processes. Since the initial discovery of SIK1 and its involvement in the cell’s ability to adapt to variation in cellular sodium concentration ( 7 , 8 ), a very complex picture of the role of individual SIK isoforms or combinations thereof has emerged as thoroughly described in recent reviews ( 1 , 2 , 9 , 10 , 11 ).

Figure 1 Domain organization of the 3 SIKs.

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“…Potent SIK inhibitors, such as HG-9-91-01 ( 12 ) and the subsequent in-vivo tool YKL-05-099 ( 13 ), have been important for understanding the biological role of the SIK kinases; however, their lack of isoform and kinome selectivity limits their use ( 12 ). Other chemical classes of potent pan-SIK inhibitors have been developed and used to further elucidate the physiological roles of SIK kinases, as summarized by Jagannath ( 2 ). Interestingly, the clinically approved tyrosine kinase inhibitors bosutinib and dasatinib, inhibit SIK at nanomolar concentrations ( 14 ).…”