Nuts and bolts of the salt-inducible kinases (SIKs).
Nuts and bolts of the salt-inducible kinases (SIKs).
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盐诱导激酶（SIKs）的基本原理。
DOI：
10.1042/bcj20200502
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发表时间：
2021-04-16
期刊：
影响因子：
--
通讯作者：
Cohen P
中科院分区：
文献类型：
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作者：
Darling NJ;Cohen P
盐诱导激酶SIK1， SIK2和SIK3与amp活化蛋白激酶（AMPK）和其他AMPK相关激酶最相似，并且与这些家族成员一样，它们需要被LKB1磷酸化才能具有催化活性。然而，与其他ampk相关的激酶不同，它们被环amp依赖性蛋白激酶（PKA）磷酸化，这促进了它们与14-3-3蛋白的结合和失活。最完善的SIKs底物是creb调控的转录共激活因子（crtc）和2a类组蛋白去乙酰化酶（HDAC4/5/7/9）。SIKs的磷酸化促进了crtc和2a类hdac向细胞质的易位及其与14-3-3的结合，阻止了它们调节其核结合伙伴转录因子CREB和MEF2。这一过程被pka依赖性SIKs失活逆转，导致crtc和2a类hdac去磷酸化并重新进入细胞核。通过这些底物和其他尚未确定的底物的可逆调节，SIKs调节许多生理过程，从先天免疫、昼夜节律和骨骼形成，到皮肤色素沉着和代谢。这篇综述总结了目前对SIK的认识和支持这些发现的证据，并讨论了SIK抑制剂治疗疾病的治疗潜力。
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.