Salt-inducible kinase in steroidogenesis and adipogenesis

Salt-inducible kinase insteroidogenesis and adipogenesisMitsuhiro Okamoto1,2, Hiroshi Takemori2 and Yoshiko Katoh2

1Laboratories for Biomolecular Networks, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita,

Osaka, 565-0871 Japan2Department of Biochemistry and Molecular Biology, Graduate School of Medicine, H-1, Osaka University, 2-2 Yamadaoka, Suita,

Osaka, 565-0871 Japan

The salt-inducible kinases (SIKs) are a family of related

serine-threonine kinases. In cultured adrenocortical cells,

SIK1 is rapidly but transiently induced by adrenocortico-

tropin (ACTH) treatment, suggesting that it contributes

to ACTH-mediated induction of steroidogenic enzymes.

However, ACTH treatment of Y1 mouse adrenocortical

cells stimulates a rapid translocation of SIK1 from the

nucleus to the cytoplasm, and SIK1 represses the tran-

scription of a steroidogenic enzyme by inhibiting the

action of cAMP-responsive elements in the promoter.

These studies suggest that SIK1 has a role in the fine

tuning of steroidogenic enzyme production during the

initial phase of steroidogenesis. SIK2 is found in adipo-

cytes and phosphorylates a specific serine residue in

insulin receptor substrate-1. This finding, along with

the fact that its expression is raised in the white adi-

pose tissue of mice with type 2 diabetes mellitus,

suggests that SIK2 might be involved in metabolic regu-

lation in adipose tissue. Thus, members of the SIK

family are emerging as important modulators of key

processes such as steroid hormone biosynthesis by the

adrenal cortex and insulin signaling in adipocytes.

Proper responses to environmental stimuli are crucial forthe maintenance of homeostasis in organisms. Hormonesplay a crucial role in this maintenance by binding to theirreceptors on the cell surface and, as a result, altering themetabolism of the cell. The physical interaction betweenthe hormone and its receptor is transduced into chemicalsignals, producing second messengers in the cell thattrigger a cascade of reactions. The cascade of reactions,which are often catalyzed by several protein kinases,eventually lead to the transcriptional regulation of specificgenes. Accordingly, the identification of a novel gene inwhich transcription is activated specifically in the earlystages of hormonal stimulation would provide new andimportant insights into the mechanisms underlying theaction of that hormone.

The plasma concentrations of Naþ and Kþ ions modu-late cell proliferation, mitochondrial density and the bio-synthesis of steroid hormones in the adrenal cortex [1,2].With the use of a PCR-coupled cDNA subtraction hybrid-ization method, a cDNA has been isolated from high-saltdiet-fed rat adrenal glands that encodes a novel protein

kinase called salt-inducible kinase (SIK) [3]. Feldman et al.independently isolated the same cDNA from membrane-depolarized PC12 rat pheochromocytoma cells [4]. Themolecular characterization of the kinase showed that itbelongs to a serine–threonine protein kinase family that iscomposed of three isoforms; the original one was namedSIK1, and the newly identified ones, SIK2 [5] and SIK3 [6].The genes encoding SIK1 and SIK2 are activated duringthe early phases of hormonal stimulation of the adrenalcortex [3,7], neural tissue [4,8] and adipose tissue [5].Further investigations of this kinase family would providenew insights into the physiology of these tissues.

The expression, structure and activity of SIK

Sik1 mRNA was cloned from adrenal glands of ratsfed with either a high-Naþ or a high-Kþ diet for a week[3]. The mRNA was seen in the capsular (zona glomeru-losa) and non-capsular (zona fasciculata/reticularis andmedulla) portions of adrenal glands from normal rats [7].It was also expressed abundantly in adrenocorticotropin(ACTH)-stimulated Y1 mouse adrenocortical tumor cells[3,7]. The mRNA was independently cloned from PC12rat pheochromocytoma cells whose membranes had beendepolarized with the use of high concentrations of Kþ [4].Therefore, the gene encoding SIK1 seems to be activated ineither the adrenal cortex or the medulla of animals keptunder certain stressful conditions. In addition to occurringin the rat adrenal gland, Sik1 mRNA was also found in thebrain (cortex and hippocampus), pituitary, ovary and lungof normal rats, although its levels in these tissues werelower than those seen in the adrenal [4,7]. Sik1 mRNAwasalso expressed in the adrenal gland, brain, ovary and testisof normal mice [5]. It appears to be expressed in the heartalso, because Ruiz et al. isolated a partial cDNA fragmentof the Sik1 as a gene expressed during murine cardiacdevelopment [9].

Based on the cDNA structure of Sik1, the human andmouse genome databases were searched for similar genes.As a result, two isoforms, SIK2 and SIK3, were identified.The SIK1 gene (SNF1LK) was localized to human chromo-some 21, whereas both SIK2 and SIK3 genes were local-ized to chromosome 11. Sik2 mRNA was expressed in bothwhite and brown adipose tissue, and, at a lower level, inthe testes of normal mice. By contrast, Sik3 expressionCorresponding author: M. Okamoto ([email protected]).

Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 2004 21

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seems to be ubiquitous, although levels of expression werelower than that seen for Sik2 mRNA in the testis [6].

SIK homologs have also been described in species otherthan humans, rat and mouse. A SIK1 homolog of chicken,QIK, was isolated from chicken embryo fibroblasts trans-formed by the qin oncogene, a forkhead/winged helixtranscription factor [10]. Kin-29 is a SIK3 homolog ofCaenorhabditis elegans that regulates the expression ofthe olfactory receptor gene [11]. Genes homologous to SIKwere also identified from the insect genome databases;thus, T13741 and AAF57652 in Drosophila melanogaster[12] encode SIK2 and SIK3, respectively, as do EAA07881and EAA11379 in Anopheles gambiae [13]. Thus far,no homologous gene has been found in the plantgenome databases.

The primary structures of SIK and its homologs areoutlined in Figure 1. SIK is a tripartite kinase containinga serine-threonine kinase domain at its N-terminal end, asucrose-nonfermenting 1 (SNF-1) kinase homology domainin its middle, and a domain containing a protein kinase A(PKA)-dependent phosphorylatable serine residue at itsC-terminal end. The sequence characteristics of its kinasedomain and the SNF-1 kinase homology domain suggestthat it belongs to the SNF/AMP-activated protein kinase(AMPK) family, a family conserved among animals, plantsand fungi, and often considered to be metabolic sensors ofthese organisms [14–19].

The full-length SIK1 and a fragment containing thekinase domain were synthesized as glutathione-S-trans-ferase-fused proteins in Escherichia coli, purified and

tested for their kinase activities in vitro. The resultsshowed that both enzymes, when incubated with ATP,could phosphorylate themselves [3]. A site(s) for thisautophosphorylation has yet to be determined. Whencommercially available peptide substrates for serine-threonine protein kinases were tested in the in vitrokinase assays, Syntide 2, but not Autocamtide 2, wasphosphorylated by SIK1 [4,7]. Histone H1 was not asubstrate [4]. As a result of a kinase assay using varioussynthetic peptide substrates, it was suggested that acanonical phosphorylation motif of SIK is (Hy)[(B)X orX(B)]XX(S)XXX(Hy), in which S is the phosphorylatableserine, and (Hy) and (B) are hydrophobic and basicresidues, respectively [5]. At present, little is knownabout the endogenous substrate of SIK, except that insulinreceptor substrate-1 (IRS-1) is phosphorylated at Ser794by SIK2 in adipocytes [5].

An ATP-binding motif was identified in the kinasedomain of SIK. When a lysine residue present in thismotif, Lys56 of SIK1 or Lys49 of SIK2 was replaced withmethionine, the resultant SIK1 (Lys56Met) or SIK2(Lys49Met) had no kinase activity, indicating that thislysine might play an important role in the catalytic activityof this enzyme [5,7].

Unlike AMPK, which is a heterotrimeric enzymecomprising a- (protein kinase), b- and g-subunits [14],and acts as a multisubunit enzyme in cells, SIK seems toact as a single subunit enzyme, because, so far, there havebeen no reports that the SIK peptide binds specifically tothe other peptide(s) in cells.

Figure 1. SIK isoforms of various animal species, with their gene accession numbers. The kinase domain (KD) is shown in green, the SNF-1 kinase homology domain in blue

and the PKA-phosphorylation site (PKA site), with the phosphorylatable serine in pink. It has not been possible to identify the SNF-1 kinase homology domain in Kin-29.

Abbreviations: PKA, protein kinase A; SIK, salt-inducible kinase; SNF, sucrose-nonfermenting.

TRENDS in Endocrinology & Metabolism

1 150 300 450 600 750 900 1050 1200Outline of primary structure

S517 6401 12 263

S56341 7021 292

S51716 8221 267

S4938 12631 259

S34617 5181 243

S1032141 13981 392

S58720 9311 271

7981 S57526 277

S577 7761 27 278

PKA siteKD

Enzyme

Kin-29

SIK3

SIK2

QIK

SIK1

Animal

Anopheles

Drosophila

Caenorhabditis

Human

Anopheles

Drosophila

Mouse

Chicken

Rat

Access No.

EAA11379

AAF57652

AF403714

AB023216

EAA07881

T13741

AB067780

JC7500

AB020480

Review TRENDS in Endocrinology and Metabolism Vol.15 No.1 January/February 200422

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SIK is induced at the early stage of hormonal stimulation

through cAMP–PKA signaling

The level of Sik1 mRNA in ACTH (1 mM)-stimulated Y1cells rapidly reached a peak within 1 h, and then graduallyfell, returning to basal levels after 12 h [7] (Figure 2). Thetime course closely coincided with that of ACTH-stimulatedSIK1 protein synthesis and kinase activity. Both forskolin(20 mM) and 8-Br-cAMP (1 mM) also acted as stimulants.mRNA expression was not influenced by the presenceof cycloheximide, suggesting that no previous proteinsynthesis was required. In Y1-derived, PKA-defective,Kin-7 cells, Sik1 mRNA expression was not seen, evenwhen the cells were incubated with ACTH, forskolin or8-Br-cAMP. However, when Kin-7 cells were transfectedwith an expression vector of the PKA catalytic subunit,they expressed Sik1 mRNA without ACTH treatment.This suggests that the expression of Sik1 mRNA occurredin Y1 cells through cAMP–PKA signaling. In contrast tothe early rise in the level of Sik1 mRNA, the levels ofsteroidogenic protein mRNAs, such as those encodingsteroidogenic acute regulatory (StAR) protein and cyto-chrome P450scc (CYP11A), were elevated later; the formerwas significantly elevated after 2 h, and the latter after8 h (Figure 2). These steroidogenic mRNAs continued toincrease until 24 h after the addition of ACTH.

The level of Sik1 mRNA in KCl (50 mM)-treated PC12cells increased rapidly, reaching a peak after 45 min, andreturned to the basal level after 2–4 h [4]. Forskolin(25 mM) was as strong a stimulant as was Kþ, whereas theCa2þ ionophore A23187 (10 mM) was a weaker stimulant.

The induction of Sik1 mRNA by the in vivo stimulationof neural activities was tested in rats suffering from drug-induced seizures. When rats were injected subcutaneously

with kainic acid (12 mg kg21), seizure was induced. Brainsremoved after the onset of seizures were subject to in situhybridization using a probe for Sik1 mRNA. The Sik1mRNA level rapidly increased within 1 h in all hippo-campal fields and also in the cortex [4]. In particular, themRNA level in the granule cells of the dentate gyrus wasincreased eightfold within 1 h and remained higher thanthe control up to 8 h after the seizure.

The time course of expression of SIK2 mRNA wasexamined during adipocyte differentiation. When 3T3-L1preadipocytes were treated with adipocyte differenti-ation medium [a mixture of 3-methyl-1-isobutylxanthine(0.5 mM), insulin (1 mg ml21) and dexamethasone (1 mM)],SIK2 mRNA levels increased within 1 h and peaked after12 h [5]. The peak level continued until day 7. The increasein SIK2 mRNA levels was very similar to that seen forearly response transcription factor mRNAs, such as thoseencoding CCAAT/enhancer-binding protein b (C/EBPb)and C/EBPd. The levels mRNA encoding late responsegenes of adipogenesis, such as those encoding SREBP-1(sterol-responsive element-binding protein), C/EBPa,PPARg (peroxisome proliferator-activated receptor g)and adipocyte-specific fatty acid-binding protein (aP2),began to increase after days 2 to 4. Among the threestimulants in the differentiation medium, dexamethasone,but not 3-methyl-1-isobutylxanthine, seemed to be aneffective stimulant for the early transcription of the SIK2gene, although more studies are needed to confirm this.

Therefore, we conclude that the SIK gene is one ofthe early response genes in adrenal steroidogenesis,neural membrane depolarization and adipocyte differen-tiation. SIK1 gene transcription seems to be mediated bycAMP–PKA signaling. Hence, the promoter region of theSIK1 gene should be analyzed to identify possible targetsite(s) of cAMP–PKA signaling.

SIK represses the cAMP-responsive element-dependent

transcription of steroidogenic genes

That the transcription of the Sik1 gene occurred transi-ently in the very early stage of ACTH stimulation andpreceded that of the steroidogenic genes (Figure 2) raisedthe question of whether SIK1 has a regulatory role(s) insteroidogenic gene expression. To answer this question,Y1 cell lines that overexpressed Sik1 were established andtheir steroidogenic gene expression examined. Surpris-ingly, the level of Cyp11a mRNA in Sik1 transformantswas significantly lower than that in nontransformants,and the level in transformants was not increased by ACTHtreatment [7]. Star mRNA in either Sik1 transformantsor nontransformants (although not seen in significantamounts before ACTH treatment) increased similarlyduring the first 2 h after the addition of ACTH, althoughthe level in Sik1 transformants after 12 h was clearlyrepressed compared with that in nontransformants.These results suggest that SIK1 might act as a repressor,rather than an activator, of steroidogenic gene tran-scription in Y1 cells.

The mechanism underlying SIK1-mediated repres-sion of steroidogenic gene transcription was furtherexplored in co-transfection experiments with the use of apromoter-linked reporter gene and the Sik1 gene. In these

Figure 2. Induction of mRNA encoding SIK1 (red) occurs earlier than that encoding

CYP11A (blue) and StAR (green). ACTH (1 mM) was added to Y1 cells at time 0,

and total RNA was extracted from the cells at the indicated times for northern blot

analyses. mRNA levels were estimated semiquantitatively, based on the data

presented in [7], and shown as ratios to those of the start points. Abbreviations:

ACTH, adrenocorticotropin; SIK, salt-inducible kinase; StAR, steroidogenic acute

regulatory protein.


0 1 2 4 8 12 24

Incubation time (h)

mR

NA

leve

l (fo

ld o

ver

basa

l)

ACTH

1

3

5

7

9

11

13

15




experiments, Y1 cells that had been transfected with asteroidogenic gene promoter-linked luciferase gene wereactivated through cAMP–PKA signaling. Any luciferaseactivity in the cell homogenates provides a measure ofPKA-dependent-activated steroidogenic gene expression.When the cells had been transfected with the Sik1 expres-sion vector, together with the steroidogenic gene promoter–luciferase gene, comparison of the luciferase activity inSik1 co-expressed cell homogenates with that in Sik1nonexpressed cell homogenates provides a measure ofthe effect of SIK1 on steroidogenic gene expression.These experiments gave the following results: (i) acAMP-responsive element (CRE)-like sequence located at21.8 to 21.5 kb in the human CYP11A gene promoter wasresponsible for the cAMP–PKA signaling-mediated acti-vation of CYP11A gene transcription [20–22]; (ii) thesame CRE-like sequence was the major target site forSIK1-mediated repression of gene transcription [23]; (iii) aprotein factor in the Y1 cell nucleus that might have boundto the CRE-like element during transcriptional activationof the CYP11A gene was identified as CRE-binding protein(CREB) [23]; (iv) a CRE-like sequence located at 295 to285 kb in the human STAR gene promoter was respon-sible for the cAMP–PKA signaling-mediated activation ofSTAR gene transcription [24,25]; (v) the same CRE-likesequence was the major target site of SIK1-mediatedrepression of gene transcription [25]; and (vi) the proteinkinase activity of SIK1 was indispensable for SIK1-mediated repression [23,25]. Together, these resultssuggest that SIK1 prevents the efficient working of theCREB-containing transcription activation complexformed on the CRE-like element in the promoter regionof steroidogenic genes. Further experiments show thatSIK1 does not phosphorylate CREB itself, but repressestranscription by a mechanism involving the basic leucinezipper domain of CREB [23,25] (Figure 3). The phos-phorylation target of SIK1 has yet to be identified,although it might be one of the components of the CREBtranscription activation complex. Therefore, by actingdirectly, or indirectly, on the transcription activationcomplex, SIK1 seems to inhibit the smooth operationof the complex.

The nucleocytoplasmic shuttling of SIK1 in

ACTH-stimulated cells

Immunocytochemical studies using anti-SIK1 antibody orfluorocytochemical analyses of green fluorescent protein(GFP)-tagged SIK1-expressing cells showed that SIK1is present both in the nuclear and cytoplasmic compart-ments of resting Y1 cells [25]. Interestingly, when the cellswere stimulated with ACTH, nuclear SIK1 moved to thecytoplasm within 15 min. This movement coincided withPKA-dependent phosphorylation of Ser577 in the SIK1peptide. Nuclear levels of SIK1 gradually returned to theirinitial levels after 12 h, with the concomitant dephos-phorylation of the peptide. The nature of the cytoplasmicphosphatase involved in this process has yet to be clarified.

These results led to the hypothesis that SIK1 couldswitch steroidogenic gene expression on and off at theinitial phase of ACTH stimulation. Thus, SIK1, present in

the nuclei of resting Y1 cells and acting as a repressor ofCRE-dependent gene transcription, would be phosphory-lated immediately after stimulation by ACTH, with theresultant phospho-SIK1 being translocated to the cyto-plasm. The decreasing levels of the repressor in the nucleiwould trigger the initiation of CRE-dependent gene tran-scription. After a few hours, the phospho-SIK1 in thecytoplasm would be dephosphorylated, and SIK1 wouldre-enter the nuclei, blocking gene transcription (Figure 3).Several experiments were conducted to test this hypothe-sis, and the results appeared to confirm this notion [25].

However, before fully understanding the physiologicalmeaning of the nucleocytoplasmic shuttling of SIK1, wemust explore the molecular basis of intracellular redis-tribution of the SIK1 protein. In particular, the domains inthe SIK1 peptide that take part in nuclear import andexport must first be determined, and the interrelationshipbetween these domains and the phospho-, or dephospho-Ser577 residue must be examined. In relation to this,the following should be noted. In 3T3-L1 preadipocytes(similar to that seen in Y1 cells), GFP-fused SIK1 waspresent mainly in the nucleus, and the protein was trans-located to the cytoplasm after the cells were stimulatedwith the adipocyte differentiation medium [5]. By contrast,GFP-fused SIK2 was found mainly in the cytoplasmiccompartment of both resting and stimulated cells, butwhen the Ser587 residue (equivalent to Ser577 in SIK1)was disrupted, the resultant GFP–SIK2 (Ser587Ala)accumulated in the nucleus [5].

Figure 3. The role of SIK1 in switching on and off steroidogenic gene expression

at the initial phase of ACTH stimulation. SIK1 in the Y1 cell nucleus represses

the CRE-dependent transcription of the CYP11A gene by inhibiting the efficient

operation of the CREB transcription activation complex. When PKA phosphory-

lates Ser577 of the SIK1 peptide, phosho-SIK1 is translocated to the cytoplasm and

the diminishing level of the repressor triggers the initiation of CYP11A gene tran-

scription. After several hours, the dephosphorylated SIK1 returns to the nucleus.

Abbreviations: ACTH, adrenocorticotropin; ACTH-R, adrenocorticotropin receptor;

bZIP, basic leucine zipper domain; cAMP-response element; CRE, cAMP-response

element; CREB, cAMP-response element-binding protein; P, organic phosphate;

PKA, protein kinase A; SIK, salt-inducible kinase.


NucleusCREB

CYP11A

Cytoplasm

577

133

SIK

RP

R

CRE

bZIP

ACTH

ACTH-R

SIK

P

P P

SIK SIK

P

SIK

PKA

PKA

S

RR

A

S

ATPcAMP

Adenylcyclase

Gprotein




The phosphorylation of Ser794 in IRS-1 by SIK2 and the

activation of SIK2 in diabetic animals

Based on the finding that SIK2 is highly expressed inmature adipocytes, attempts were made to look for sub-strates of SIK2 that might be phosphorylated in insulin-stimulated adipose tissues. Because IRS-1 has a canonicalphosphorylation motif for SIK action, the ability of SIK2 tophosphorylate IRS-1 was tested. Ser794 in human IRS-1,the equivalent of Ser789 in rat IRS-1, could be phosphory-lated by SIK2 both in 3T3-L1 adipocytes and COS-7 cells[5]. Numerous recent reports have suggested that undercertain pathological conditions IRS proteins are phosphory-lated on serine residues, and that the phosphorylated IRSproteins modulate the efficiency of the insulin-signalingcascade, eventually rendering the animals resistant toinsulin stimulation [26–30] (Figure 4). Therefore, the levelof SIK2 was tested in various tissues of type 2 diabeticanimals. SIK2 activity and protein concentrations wereindeed raised in white adipose tissue from db/db diabeticmice [5]. By contrast, Sik1 mRNA, although its tissuedistribution was mainly restricted to the adrenal glands ofwild-type animals, was markedly increased in brown adi-pose tissue, liver and skeletal muscle in diabetic animals[5]. These findings suggest that both SIK1 and SIK2 mightplay important roles in the regulation of biological fuelmetabolism under certain pathological conditions.

Summary and future research

The recently identified protein kinase SIK is present athigh levels in the adrenal cortex, adrenal medulla, neuraltissues and adipose tissues. When the cAMP–PKA signal-ing system is activated in these tissues, SIK levels increase

rapidly, reaching a peak within 1 h, and gradually return-ing to basal levels after several hours. The expression ofSik1 in ACTH-stimulated adrenocortical cells precedes theexpression of steroidogenic proteins. SIK1 also repressessteroidogenic gene transcription by inhibiting efficientoperation of the CREB-containing transcription activa-tion complex formed on the CRE-like element in thepromoter of steroidogenic genes. SIK1 also engages inrapid nucleocytoplasmic shuttling in ACTH-stimulatedY1 cells. Together, these results suggest that SIK1 mightdetermine the precise timing of steroidogenic gene expres-sion in the initial phase of ACTH stimulation.

The adipose-specific SIK2 protein phosphorylates Ser794in IRS-1. The increased expression of Sik2 in the whiteadipose tissue of type 2 diabetic mice strongly suggeststhat SIK2 might be involved in the regulation of biologicalfuel metabolism in adipose tissue.

The following issues still need to be addressed if we areto understand this system more completely: (i) althoughIRS-1 is a potential endogenous substrate of SIK2, arethere other intracellular target(s) that would be phos-phorylated by SIK during the hormonal stimulation ofendocrine tissues? The identification of such substrateswould give crucial insights into the physiological rolesplayed by SIK; (ii) a search should be made for anintracellular protein(s) that interacts with SIK. Thisprotein might regulate the enzyme activity of SIKor, conversely, SIK might regulate the intracellularfunction of that protein. The target molecule of SIKaction in the CREB-containing transcription activationcomplex, for instance, might be one of the transcriptionalco-regulator proteins. The direct interaction of the puta-tive co-regulator with SIK, and its possible phosphoryl-ation by SIK, might result in the transcription repression;(iii) the autophosphorylation site of SIK must be deter-mined, because the enzymatic activity of SIK, similar tothat of AMPK, might be precisely regulated by its ownphosphorylation state; (iv) the physiological role of SIK3,the ubiquitous SIK family kinase, remains to be explored;(v) knowledge of the role played by SIK would be greatlyadvanced by successful development and examination ofSik gene transgenic, or Sik gene-disrupted, animals.

Finally, because the abnormal expression of SIK familyprotein kinases might cause severe endocrine disorderssuch as defective steroid hormone biosynthesis and defec-tive glucose and fat metabolism, these kinases mightbecome important therapeutic targets for these disordersin the future.

AcknowledgementsThe authors are supported by grants-in-aid for Scientific Research fromthe Ministry of Education, Culture, Science, and Technology, the Ministryof Health, Labor and Welfare Japan, a grant from The Uehara MemorialFoundation, The Salt Science Research Foundation Grant 0238, and ‘21stCentury Center of Excellence’ grant of Japan.

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Figure 4. The role of SIK2 in modulating insulin signaling in the adipocyte. When

insulin binds to its receptor on the cell surface, the tyrosine phosphorylation

cascade is initiated. The resultant tyrosine-phosphorylated, activated IRS-1 is a

major player in insulin signaling, and eventually produces the lipogenic response.

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Abbreviations: Insulin-R, insulin receptor; IRS, insulin receptor substrate; SIK,

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Insulin

Insulin-R

–Y

Y

Y–

S

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SIK

P P

P

PIRS-1




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enabling you to keep abreast with advances across the life sciences.

Written by laboratory scientists with a keen understanding of their field, Research Update will clarify the significance

and future impact of this research.

Our experienced in-house team is under the guidance of a panel of experts from across the life sciences

who offer suggestions and advice to ensure that we have high calibre authors and have spotted

the ‘hot’ papers.

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Documents

Salt-inducible kinase in steroidogenesis and adipogenesis