Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet‐treated rat adrenal 1

Salt-inducible kinase (SIK), one of the AMP-activated kinase (AMPK)-related kinases, has been suggested to play important functions in glucose homeostasis by inhibiting the cAMP-response element-binding protein (CREB)-regulated transcription coactivator (CRTC). To examine the role of SIK in vivo,we generated Drosophila SIK mutant and found that the mutant flies have higher amounts of lipid and glycogen stores and are resistant to starvation. Interestingly, SIK transcripts are highly enriched in the brain, and we found that neuron-specific expression of exogenous SIK fully rescued lipid and glycogen storage phenotypes as well as starvation resistance of the mutant. Using genetic and biochemical analyses, we demonstrated that CRTC Ser-157 phosphorylation by SIK is critical for inhibiting CRTC activity in vivo. Furthermore, double mutants of SIK and CRTC became sensitive to starvation, and the Ser-157 phosphomimetic mutation of CRTC reduced lipid and glycogen levels in the SIK mutant, suggesting that CRTC mediates the effects of SIK signaling. Collectively, our results strongly support the importance of the SIK-CRTC signaling axis that functions in the brain to maintain energy homeostasis in Drosophila. Salt-inducible kinase (SIK)2 was first cloned from adrenal glands of rats fed with a high salt diet (1), and its transcription was strongly induced by membrane depolarization in the brain (2). Recent studies unexpectedly demonstrated that SIK1 also plays important functions in liver glucose homeostasis (3) and survival of myocytes (4). Furthermore, SIK1 is involved in TGF-␤ signaling (5) and histone deacetylase regulation (6), supporting highly diverse functions in mammalian systems.Through genomic database analyses, SIK2 (Qin-induced kinase (QIK)) and SIK3 (QSK) were identified as SIK family members based on their structural homologies to SIK1 (7). Interestingly, SIK family kinases belong to AMP-activated protein kinase (AMPK)-related kinases, which are activated by LKB1 (8, 9). Based on this conserved regulation of SIK and other AMPK-related kinases, SIK is believed to have highly specialized downstream targets to differentially function in the cell. However, due to the lack of loss-of-function animal models, the in vivo functions of SIK remain elusive, in contrast to the well characterized functions of AMPK.The members of CREB-regulated transcription coactivator (CRTC), also known as TORC (transducer of regulated CREB), are newly identified CREB co-activators (10, 11). Under the basal condition, phosphorylated CRTC is sequestered in the cytoplasm. However, in response to increased levels of calcium and cAMP, CRTC is dephosphorylated and subsequently translocated to the nucleus, which leads to the activation of cAMP-response element (CRE)-mediated gene transcription by association with CREB (12, 13). Recent studies demonstrated that one of the family members, CRTC2, has a crucial function in the gluconeogenic program in the liver (3,14). SIK and AMPK repress CRE transcriptional responses by phosphorylating CRTC2 a...

Section: Salt-inducible Kinase (Sik)mentioning

confidence: 99%

Drosophila Salt-inducible Kinase (SIK) Regulates Starvation Resistance through cAMP-response Element-binding Protein (CREB)-regulated Transcription Coactivator (CRTC)

Choi

Kim

Chung

2011

“…Because our anti-SIK1 antibody cross-reacted with SIK2 protein, we could not determine the content and activity of SIK1 protein in these tissues. However, a possibility remains that SIK1, which was originally described as "salt-inducible kinase" (26), might be the kinase responsible for phosphorylation of Ser 789 in IRS-1 in the livers of diabetic animals. Taken together, we propose here that in the diabetic animals, SIK2 in white adipose tissues and SIK1 in brown adipose tissues, livers, and skeletal muscles might be involved in the disturbance of the insulin signaling occurring in these tissues and therefore might play important pathogenic roles in the development of type 2 diabetes.…”

Section: Sik2 Is Activated In White Adipose Tissues Of Diabetic Mice-mentioning

confidence: 99%

“…The serine phosphorylation of IRS proteins would modulate the efficiency of the insulinsignaling cascade (8, 9) and eventually render the animals resistant to insulin stimulation (10, 11). Molecular identification of several protein kinases responsible for the serine phosphorylation of IRS proteins has been reported (12-24).Salt-inducible kinase (SIK) was first cloned from the adrenal glands of rats fed a high salt diet (25,26). It is a serine/ threonine protein kinase that belongs to a sucrose-nonfermenting-1 protein kinase/AMP-activated protein kinase (AMPK) family.…”

mentioning

confidence: 99%

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Adipose-specific Expression, Phosphorylation of Ser794 in Insulin Receptor Substrate-1, and Activation in Diabetic Animals of Salt-inducible Kinase-2

Horike

Takemori

Katoh

et al. 2003

Self Cite

138

179

Salt-inducible kinase (SIK), first cloned from the adrenal glands of rats fed a high salt diet, is a serine/threonine protein kinase belonging to an AMP-activated protein kinase family. Induced in Y1 cells at an early stage of ACTH stimulation, it regulated the initial steps of steroidogenesis. Here we report the identification of its isoform SIK2. When a green fluorescent protein-fused SIK2 was expressed in 3T3-L1 preadipocytes, it was mostly present in the cytoplasm. When coexpressed in cAMP-responsive element-reporter assay systems, SIK2 could repress the cAMP-responsive element-dependent transcription, although the degree of repression seemed weaker than that by SIK1. SIK2 was specifically expressed in adipose tissues. When 3T3-L1 cells were treated with the adipose differentiation mixture, SIK2 mRNA was induced within 1 h, the time of induction almost coinciding with that of c/EBP␤ mRNA. Coexpressed with human insulin receptor substrate-1 (IRS-1) in COS cells, SIK2 could phosphorylate Ser 794 of human IRS-1. Adenovirus-mediated overexpression of SIK2 in adipocytes elevated the level of phosphorylation at Ser 789 , the mouse equivalent of human Ser 794 . Moreover, the activity and content of SIK2 were elevated in white adipose tissues of db/db diabetic mice. These results suggest that highly expressed SIK2 in insulin-stimulated adipocytes phosphorylates Ser 794 of IRS-1 and, as a result, might modulate the efficiency of insulin signal transduction, eventually causing the insulin resistance in diabetic animals.The lipid metabolism in adipose tissues is under the control of two hormonal signaling pathways; insulin stimulates glucose uptake and lipogenesis, whereas cAMP, generated by exogenous stimuli like adrenalin and glucagon, stimulates lipolysis. If the balance between the two signaling systems becomes lost and the adipose tissues are exposed to hyperinsulinemia for a prolonged time, they gradually become resistant to insulin stimulation (1, 2). The insulin resistance occurring in tissues involved in biological fuel metabolism, such as adipose tissues, liver, and skeletal muscles, would finally cause disorders in energy metabolism of the whole body, such as obesity and type 2 diabetes (3, 4). Insulin receptor substrate (IRS) 1 proteins are key molecules of the insulin-signaling cascade (5); they are phosphorylated on tyrosine residues by the action of insulindependently activated insulin receptor kinase, and the tyrosine-phosphorylated IRS proteins trigger further intracellular cascades. Several investigators recently reported (6, 7) that IRS proteins, under certain non-physiological conditions, were phosphorylated on serine residues. The serine phosphorylation of IRS proteins would modulate the efficiency of the insulinsignaling cascade (8, 9) and eventually render the animals resistant to insulin stimulation (10, 11). Molecular identification of several protein kinases responsible for the serine phosphorylation of IRS proteins has been reported (12-24).Salt-inducible kinase (SIK) was first cloned from ...

“…Salt-inducible kinase (SIK) was identified as a serine/threonine protein kinase induced in the adrenal glands of high-salt diet-fed rats (33,34). When Y1 mouse adrenocortical tumor cells were incubated with ACTH, the cellular levels of mRNA, protein, and kinase activity of SIK were elevated within 1 h through the cAMP/PKA signaling mechanism, and then after a few hours the levels declined (35).…”

mentioning

confidence: 99%

ACTH-induced Nucleocytoplasmic Translocation of Salt-inducible Kinase

Takemori¹,

Katoh²,

Horike³

et al. 2002

Self Cite

Salt-inducible kinase (SIK),Extracellular hormonal stimuli, received at the cell surface by the corresponding receptors, are transduced into several chemical messengers in the cytoplasm and regulate the transcription of genes in the nuclei. Adrenocorticotropic hormone (ACTH), 1 binding to its receptor on the adrenocortical cell surface, activates adenylate cyclase and increases intracellular cAMP, which in turn activates the cAMP-dependent protein kinase (PKA) (1-3). The activated PKA then promptly stimulates the biosynthesis and secretion of steroid hormone. This is achieved through stimulation of several intracellular events; PKA activates cholesterol esterases (4 -7), thus increasing the intracellular cholesterol pool, and elevates the levels of transcription (8, 9), mRNA stability (10), translation (8), and posttranslational modification (11-15) of the steroidogenic acute regulatory (StAR) protein (16). This accelerates the transport of cholesterol from the outer to inner mitochondrial membranes, which activates the side chain cleavage cytochrome P450 (CYP11A) reaction (17-21). The resultant elevation of the plasma glucocorticoid level acts as a negative signal on the ACTH secretion from the pituitary gland, thus completing the feedback regulatory loop of the hypothalamic-pituitary-adrenocortical axis (22, 23). Several signaling molecules (24 -30) other than those mentioned above, such as phosphodiesterase (31) and protein phosphatase (32) have also been implicated in regulating steroidogenesis, indicating that the steroidogenic cells are equipped with finely tuned signal transducing systems. However, the precise mechanism underlying the acute regulation of steroidogenic gene expression, including the molecular events occurring during the initiation, maintenance, and termination of the steroidogenic gene transcription, is as yet not well understood.Salt-inducible kinase (SIK) was identified as a serine/threonine protein kinase induced in the adrenal glands of high-salt diet-fed rats (33, 34). When Y1 mouse adrenocortical tumor cells were incubated with ACTH, the cellular levels of mRNA, protein, and kinase activity of SIK were elevated within 1 h through the cAMP/PKA signaling mechanism, and then after a few hours the levels declined (35). In contrast, the transcription of StAR and CYP11A genes begin later, at a time coinciding * This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and Ministry of Health, Labor and Welfare Japan and grants from The Uehara Memorial Foundation and from The Ichiro Kanehara Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.□ S The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.ʈ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular B...