Abstract
Salt-inducible kinases (SIKs) belong to AMP-activated protein kinase (AMPK) family, and functions mainly involve in regulating energy response-related physiological processes, such as gluconeogenesis and lipid metabolism. However, compared with another well-established energy-response kinase AMPK, SIK roles in human diseases, especially in diabetes and tumorigenesis, are rarely investigated. Recently, the pilot roles of SIKs in tumorigenesis have begun to attract more attention due to the finding that the tumor suppressor role of LKB1 in non-small-cell lung cancers (NSCLCs) is unexpectedly mediated by the SIK but not AMPK kinases. Thus, here we tend to comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for SIKs, and shed light on SIKs as the potential therapeutic targets for cancer therapies.
Highlights
REVIEW ARTICLE OPENThe potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis
Salt-inducible kinase (SIK) was first identified in the adrenal glands of high salt diet-fed rats in 1999.1 Further, the SIK family members, including SIK1–SIK3, are characterized as serine/ threonine kinases that belong to AMP-activated protein kinase (AMPK) family.[2,3] Later, SIKs have shown self-phosphorylation, and play an important role in regulating adrenocortical function under the stimulation of high salt or adreno-cortico-tropichormone (ACTH).[1]
These results together show that SIK1 or SIK3 may play an important role in promoting the anti-inflammatory phenotypes, which is opposite to the function of SIK2.91,92
Summary
The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis. SIK2 (GLUT).[106] The majority of peripheral glucose uptake in adipose promotes fatty acid synthesis by upregulating SREBP1c exprestissue and skeletal muscle are achieved by insulin-responsive sion, promoting the transcription of Fasn in ovarian cancer glucose transporter 4 (GLUT4).[106] Importantly, GLUT4 expression cells.[93] Meantime, SIK2 promotes cholesterol synthesis by has been negatively regulated by various upstream regulators, upregulating SREBP2 expression, to transcriptionally elevate including but not limited to HDAC4, CRTC2/3, and protein cholesterol synthetase, 3-hydroxy-3-methyl-glutaryl-coenzyme A phosphatase 2A (PP2A).[107] These proteins are all well- reductase (HMGCR).[93] Importantly, SIK2 phosphorylated and established SIK2 downstream substrates, indicating that SIK2 is a inhibited p300 activity, leading to the decreased acetylation of positive regulator of glucose intake by upregulating GLUT4 expression (Fig. 2).[107,108,109] CREB upregulated the carbohydrate response element-binding protein (ChREBP), which plays a positive role in lipogenic and gluconeogenesis.[60] SIK2 expression of transcriptional repressor activating transcription factor 3 (ATF3), and thereby downregulated the GLUT4, resulting in promoting insulin resistance.[107,110] Consistently, inactivating SIK pharmacologically or genetically could reduce GLUT4 expression and glucose uptake.[107,108,109] SIK1 promotes insulin phosphorylated IRS-1 to attenuate insulin driven lipogenesis in human adipocytes.[55] Another study showed depletion of SIK2 promoted increased adipogenic potential and insulin resistance in preadipocytes in a CRTC2-dependent manner.[110] SIK2 controlled. Some studies showed that Sik[2] KO mice do not impact lipid metabolism in vivo.[33]
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