The Salt-Inducible Kinases: Emerging Metabolic Regulators Kei Sakamoto, Laurent Bultot, Olga Göransson  Trends in Endocrinology & Metabolism  Volume 29, Issue 12, Pages 827-840 (December 2018) DOI: 10.1016/j.tem.2018.09.007 Copyright © 2018 The Authors Terms and Conditions

Figure 1 Functional Role and Molecular Targets of SIKs in Pancreatic β-Cells. Recent studies have suggested opposing roles for salt-inducible kinase (SIK)1 and SIK2 in regulating β-cell function. SIK1 has been shown to attenuate insulin secretion by lowering cellular cAMP levels through phosphorylation and thereby activation of phosphodiesterase 4D (PDE4D). By contrast, SIK2 is required to promote insulin secretion. SIK2 acts through phosphorylation (P) of the cyclin-dependent protein kinase 5 (CDK5) activator p35 and as a result is ubiquitinated and targeted for proteasomal degradation. Reduction of p35 protein levels leads to inactivation of CDK5, resulting in less inhibitory phosphorylation of the voltage-dependent Ca2+ channel (VDCC). This causes increased Ca2+ influx and insulin secretion in response to glucose. Trends in Endocrinology & Metabolism 2018 29, 827-840DOI: (10.1016/j.tem.2018.09.007) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Functional Role and Molecular Targets of SIKs in Liver. Salt-inducible kinases (SIKs) function as a molecular brake on hepatic gluconeogenesis. Liver kinase B1 (LKB1) constitutively activates SIKs through phosphorylation of a threonine residue in the activation loop of their kinase domain. This leads to phosphorylation of target transcriptional regulators, CREB-regulated transcription coactivators (CRTCs) and histone deacetylases (HDACs), resulting in inhibition of the gluconeogenic gene program. LKB1 deficiency or pharmacological inhibition of SIKs (e.g., via HG-9-91-01) promotes dephosphorylation of CRTCs and HDACs, leading to enhanced gluconeogenic gene expression. Trends in Endocrinology & Metabolism 2018 29, 827-840DOI: (10.1016/j.tem.2018.09.007) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Functional Role and Molecular Targets of SIK2 in Adipocytes. Salt-inducible kinase (SIK)2 has been proposed as a negative regulator of lipogenic gene expression such as ACC2, FAS, and SCD1 in mouse adipocytes. The upregulation of lipogenic gene expression due to reduction or lack of SIK2 was associated with higher accumulation of triglycerides in adipocytes/adipose tissue. The molecular target(s) mediating the inhibitory effect of SIK2 on lipogenic genes is not known, but sterol regulatory element-binding proteins (SREBPs) have been proposed. SIK2 silencing or pharmacological inhibition leads to a reduction in glucose uptake in both rodent and human adipocytes. In rodents, the mechanism(s) includes positive effects of SIK2 on GLUT4 expression, whereas in human adipocytes, SIK silencing or inhibition did not affect GLUT expression, but reduced the activating phosphorylation of protein kinase B (PKB/Akt). The known substrates of SIK2 in adipocytes identified so far are CREB-regulated transcription coactivator (CRTC)2, CRTC3, and histone deacetylase (HDAC)4. These transcriptional regulators have been implicated in mediating the positive effects of SIK2 on GLUT4 expression observed in rodent cells. ACC2, acetyl-CoA carboxylase 2; CREB; cAMP response element-binding protein; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase-1. Trends in Endocrinology & Metabolism 2018 29, 827-840DOI: (10.1016/j.tem.2018.09.007) Copyright © 2018 The Authors Terms and Conditions

Figure I Domain Structure and Reported Phosphorylation Sites of SIK Isoforms. Schematic representation of human salt-inducible kinase (SIK)1 (NCBI Ref Seq NP_775490.2), SIK2 (NCBI Ref Seq NP_056006), and SIK3 (NCBI Ref Seq XP_005271538.1) proteins with conserved domains, identified phosphorylation sites, and proposed upstream kinases. Amino acid numbers based on an alternative, shorter SIK3 sequence (NCBI Ref Seq NP_079440.2) used by some groups [22,51,72], are shown within parentheses. UBA, ubiquitin-associated domain. Trends in Endocrinology & Metabolism 2018 29, 827-840DOI: (10.1016/j.tem.2018.09.007) Copyright © 2018 The Authors Terms and Conditions