Abstract
The salt-inducible kinases, SIK1, SIK2 and SIK3, most closely resemble the AMP-activated protein kinase (AMPK) and other AMPK-related kinases, and like these family members they require phosphorylation by LKB1 to be catalytically active. However, unlike other AMPK-related kinases they are phosphorylated by cyclic AMP-dependent protein kinase (PKA), which promotes their binding to 14-3-3 proteins and inactivation. The most well-established substrates of the SIKs are the CREB-regulated transcriptional co-activators (CRTCs), and the Class 2a histone deacetylases (HDAC4/5/7/9). Phosphorylation by SIKs promotes the translocation of CRTCs and Class 2a HDACs to the cytoplasm and their binding to 14-3-3s, preventing them from regulating their nuclear binding partners, the transcription factors CREB and MEF2. This process is reversed by PKA-dependent inactivation of the SIKs leading to dephosphorylation of CRTCs and Class 2a HDACs and their re-entry into the nucleus. Through the reversible regulation of these substrates and others that have not yet been identified, the SIKs regulate many physiological processes ranging from innate immunity, circadian rhythms and bone formation, to skin pigmentation and metabolism. This review summarises current knowledge of the SIKs and the evidence underpinning these findings, and discusses the therapeutic potential of SIK inhibitors for the treatment of disease.
Highlights
The AMP-activated protein kinase (AMPK) is one of the most studied protein kinases, the huge interest in this enzyme stemming from the discovery that it is a key sensor of cellular energy charge and one of the intracellular targets of metformin, the drug used most commonly to treat Type 2 diabetes [1,2,3]
The first member was identified over 20 years ago when rats fed on a high salt diet were found to induce a protein kinase in adrenal cortical tissue [4], initially termed salt-inducible kinases (SIKs), but later SIK1 when two other protein kinases with closely related catalytic domains were identified, which are called SIK2 and SIK3 [5,6]
The liver kinase B1 (LKB1)-dependent phosphorylation of SIK1 and SIK3 has been reported to create a 14-3-3 binding site [34] and may underlie the low level of 14-3-3 binding observed in cells not exposed to cyclic AMP-elevating agents; there is a substantial increase in 14-3-3 binding to SIK1, SIK2 and SIK3 detected following protein kinase (PKA)-dependent phosphorylation [26,27,30]
Summary
Unlike other AMPK-related kinases they are phosphorylated by cyclic AMP-dependent protein kinase (PKA), which promotes their binding to 14-3-3 proteins and inactivation. The most well-established substrates of the SIKs are the CREB-regulated transcriptional co-activators (CRTCs), and the Class 2a histone deacetylases (HDAC4/5/7/9). Phosphorylation by SIKs promotes the translocation of CRTCs and Class 2a HDACs to the cytoplasm and their binding to 14-3-3s, preventing them from regulating their nuclear binding partners, the transcription factors CREB and MEF2. This process is reversed by PKA-dependent inactivation of the SIKs leading to dephosphorylation of CRTCs and Class 2a HDACs and their re-entry into the nucleus.
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