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

Abstract

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/EBPβ mRNA. Coexpressed with human insulin receptor substrate-1 (IRS-1) in COS cells, SIK2 could phosphorylate Ser794 of human IRS-1. Adenovirus-mediated overexpression of SIK2 in adipocytes elevated the level of phosphorylation at Ser789, the mouse equivalent of human Ser794. Moreover, the activity and content of SIK2 were elevated in white adipose tissues ofdb/db diabetic mice. These results suggest that highly expressed SIK2 in insulin-stimulated adipocytes phosphorylates Ser794 of IRS-1 and, as a result, might modulate the efficiency of insulin signal transduction, eventually causing the insulin resistance in diabetic animals. 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/EBPβ mRNA. Coexpressed with human insulin receptor substrate-1 (IRS-1) in COS cells, SIK2 could phosphorylate Ser794 of human IRS-1. Adenovirus-mediated overexpression of SIK2 in adipocytes elevated the level of phosphorylation at Ser789, the mouse equivalent of human Ser794. Moreover, the activity and content of SIK2 were elevated in white adipose tissues ofdb/db diabetic mice. These results suggest that highly expressed SIK2 in insulin-stimulated adipocytes phosphorylates Ser794 of IRS-1 and, as a result, might modulate the efficiency of insulin signal transduction, eventually causing the insulin resistance in diabetic animals. insulin receptor substrate-1 salt-inducible kinase adrenocorticotropic hormone cAMP-response element CCAAT/enhancer-binding protein AMP-activated protein kinase green fluorescent protein glutathioneS-transferase Dulbecco's modified Eagle's medium cAMP-dependent protein kinase CRE-binding protein tumor necrosis factor-α white adipose tissue brown adipose tissue expression tag 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 (1Sul H.S. Smas C.M. Wang D. Chen L. Prog. Nucleic Acids Res. Mol. Biol. 1998; 60: 317-345Crossref PubMed Google Scholar, 2Saltiel A.R. Kahn C.R. Nature. 2001; 414: 799-806Crossref PubMed Scopus (3973) Google Scholar). 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 (3Zick Y. Trends Cell Biol. 2001; 11: 437-441Abstract Full Text PDF PubMed Scopus (186) Google Scholar, 4Lewis G.F. Carpentier A. Adeli K. Giacca A. Endocr. Rev. 2002; 23: 201-229Crossref PubMed Scopus (829) Google Scholar). Insulin receptor substrate (IRS)1 proteins are key molecules of the insulin-signaling cascade (5White M.F. Yenush L. Curr. Top. Microbiol. Immunol. 1998; 228: 179-208Crossref PubMed Google Scholar); they are phosphorylated on tyrosine residues by the action of insulin-dependently activated insulin receptor kinase, and the tyrosine-phosphorylated IRS proteins trigger further intracellular cascades. Several investigators recently reported (6White M.F. Diabetologia. 1997; 40 Suppl. 2: 2-17Crossref PubMed Scopus (465) Google Scholar, 7Saltiel A.R. Cell. 2001; 104: 517-529Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar) 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 insulin-signaling cascade (8Xiang X. Yuan M. Song Y. Ruderman N. Wen R. Luo Z. Mol. Endocrinol. 2002; 16: 552-562Crossref PubMed Scopus (49) Google Scholar, 9Greene M.W. Garofalo R.S. Biochemistry. 2002; 41: 7082-7091Crossref PubMed Scopus (88) Google Scholar) and eventually render the animals resistant to insulin stimulation (10Petersen K.F. Shulman G.I. Am. J. Cardiol. 2002; 90: G11-G18Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 11White M.F. Am. J. Physiol. 2002; 283: E413-E422Crossref PubMed Scopus (44) Google Scholar). 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 (25Halder S.K. Takemori H. Hatano O. Nonaka Y. Wada A. Okamoto M. Endocrinology. 1998; 139: 3316-3328Crossref PubMed Scopus (90) Google Scholar, 26Wang Z. Takemori H. Halder S.K. Nonaka Y. Okamoto M. FEBS Lett. 1999; 453: 135-139Crossref PubMed Scopus (119) Google Scholar). It is a serine/threonine protein kinase that belongs to a sucrose-nonfermenting-1 protein kinase/AMP-activated protein kinase (AMPK) family. It was induced in adrenocortical cells at a very early phase of ACTH stimulation, and its molecular properties have been investigated in detail (27Lin X. Takemori H. Katoh Y. Doi J. Horike N. Makino A. Nonaka Y. Okamoto M. Mol. Endocrinol. 2001; 15: 1264-1276Crossref PubMed Scopus (53) Google Scholar, 28Doi J. Takemori H. Lin X.-Z. Horike N. Katoh Y. Okamoto M. J. Biol. Chem. 2002; 277: 15629-15637Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 29Takemori H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Its presence in tissues other than the adrenal cortex was also reported (27Lin X. Takemori H. Katoh Y. Doi J. Horike N. Makino A. Nonaka Y. Okamoto M. Mol. Endocrinol. 2001; 15: 1264-1276Crossref PubMed Scopus (53) Google Scholar). Examining the genomic data base, we noticed the presence of an isoform of SIK. A cDNA clone of the isoform was isolated; the newly identified enzyme was named SIK2, and the previously reported isoform was renamed SIK1. We demonstrate here that SIK2 was abundantly expressed in adipose tissues and was induced at a very early stage during the process of preadipocyte-adipocyte differentiation. When expressed together with human IRS-1 in COS-7 cells, it phosphorylated Ser794 of human IRS-1. Moreover, its activity and content in white adipose tissues of diabetic animals were elevated. Male ddY, C57BL/6Cr, and C57BLKs/Jdb/db (30Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2112) Google Scholar) mice (10 weeks old) were purchased from SLC Co. Ltd. (Shizuoka, Japan) and maintained under standard conditions of light and temperature. All experiments were carried out in accordance with guidelines for animal care of Osaka University Medical School. By searching human genome data base GenBankTM/EMBL/DDBJ for SIK homolog, we found that the putative protein kinase KIAA0781 (GenBankTMaccession number AB018324) and SIK1 were rather similar to each other, although the COOH-terminal half of KIAA0781 seemed completely different from SIK1. We examined the chromosomal loci of human SIK1and KIAA0781 genes; the SIK1 gene was found on chromosome 21 (GenBankTM whereas the KIAA0781 gene was found on chromosome (GenBankTM number that the two were similar the KIAA0781 protein from the data base its we to a cDNA of KIAA0781 the of expressed human was than that of mouse a mouse expression tag clone data base was for mouse of the two the result, a cDNA of mouse SIK1 (GenBankTM number and that of mouse KIAA0781 protein (GenBankTM number were on the cDNA a of mouse SIK1 cDNA was by by and clone a of mouse was purchased from By cDNA as we found that mouse mRNA for KIAA0781 protein was abundantly expressed in white adipose tissues. we a mouse KIAA0781 protein cDNA with by and was by of the of an clone (GenBankTM number similar to human KIAA0781 protein and to the a was to the of the to the of cDNA several expression on the of we could the presence of the the was to have a at the The were cloned that were All the and were and to the of human KIAA0781 protein and We named the protein by cDNA and it for further The of mouse SIK2 was to that of human KIAA0781 protein and was to that of SIK1. for green protein SIK2 and SIK2, of mouse SIK2 cDNA were cloned the of H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) and by Lee A. Medical A. D. A.R. Res. 2002; PubMed Scopus Google were with the and to and expression for IRS-1 and a were by of of are as for and for and a expression for human and were by in human IRS-1 cDNA at the and the M. M. H. Y. K. M. Y. M. Y. Y. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The human IRS-1 cDNA was by and of A for human was by by an cDNA for mouse and were by from mouse adipose by the for and and for and The were cloned cDNA for and were were previously Endocr. J. 2001; PubMed Scopus Google Scholar, H. H. J. Cell 2002; PubMed Scopus Google Scholar). A to SIK2 was a at the COOH-terminal in as H. L. Hatano O. Okamoto M. H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the a cDNA the was by with and and cloned of of IRS-1 was R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). tissues were in 2 of H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The were with of at for to The was at for and the was and the protein was with The protein from white from brown from liver, from skeletal muscles, were with of and of at for The was by at for with 1 of and with 1 of (27Lin X. Takemori H. Katoh Y. Doi J. Horike N. Makino A. Nonaka Y. Okamoto M. Mol. Endocrinol. 2001; 15: 1264-1276Crossref PubMed Scopus (53) Google Scholar). The was in the with a of of the were for the and in kinase the from cells, 3T3-L1 adipocytes were in 1 of and of the were with IRS-1 (10 (10 in the presence of of for cells, from were maintained in Dulbecco's modified Eagle's medium and at under an of the cells were treated with a differentiation Z. M. PubMed Scopus Google 1 and 1 in high of glucose the 2 of the cells were high and the medium was COS-7 cells were also maintained in of expression was in The phosphorylation of Ser794 in human IRS-1 by SIK2 in COS-7 cells was by a previously H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) with COS-7 cells, been with and were with for in IRS-1 expressed in the cells was a and to by SIK2 protein in 3T3-L1 expression was cDNA of SIK2, and were and of and the were to 1 of were for of 3T3-L1 adipocytes in of proteins and COS-7 cells and was (27Lin X. Takemori H. Katoh Y. Doi J. Horike N. Makino A. Nonaka Y. Okamoto M. Mol. Endocrinol. 2001; 15: 1264-1276Crossref PubMed Scopus (53) Google Scholar, 29Takemori H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). for in kinase and were in X. Takemori H. Katoh Y. Doi J. Horike N. Makino A. Nonaka Y. Okamoto M. Mol. Endocrinol. 2001; 15: 1264-1276Crossref PubMed Scopus (53) Google SIK2 is a with a molecular the between mouse SIK2 and highly a serine/threonine protein kinase was found the of SIK2, at the residues. residues in the SIK2 and SIK1 kinase were to each a with residues between SIK2 and was found in the of the A data base that a a found in several proteins with intracellular protein 2 a for the intracellular of SIK protein to present from the a protein kinase a SIK2 equivalent for of SIK1. SIK2 and SIK1 were expressed as proteins in COS-7 cells and by a The were to by the The expressed an molecular of the of and SIK2 in The was with 2 in the presence of and the was to by in on an and the with the molecular was that of the phosphorylated whereas that with the molecular was that of the SIK2. of SIK2, present in the in is an SIK2 equivalent to of SIK1 that was for the kinase A SIK2 of was for the kinase with the results of the The similar experiments with SIK1 the results completely with reported of SIK1 that it was present in and of Y1 with the content in the H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). was that the cells were with was protein kinase and the phosphorylated SIK1 was to the cytoplasm. We examined the of SIK1 and SIK2 by in 3T3-L1 cells expressed in 3T3-L1 cells, like that expressed in Y1 cells, was mostly present in the and the protein was to the the cells were with a differentiation seemed to mostly in the of and cells, although green signal could in the as SIK2 was in present in the was in the cells been with coexpressed with gene in Y1 cells, could repress the activated activity J. Takemori H. Lin X.-Z. Horike N. Katoh Y. Okamoto M. J. Biol. Chem. 2002; 277: 15629-15637Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). We examined the of on efficiency in 3T3-L1 cells by The of of the of was weaker in with by SIK1 in phosphorylation been could repress the activity than the SIK2. The SIK kinase activity was for the to The tissue of SIK2 was examined by of tissues from mice of SIK2 were found in white adipose and brown adipose tissues, and a was found in the SIK2 mRNA and were seemed to from an reported (27Lin X. Takemori H. Katoh Y. Doi J. Horike N. Makino A. Nonaka Y. Okamoto M. Mol. Endocrinol. 2001; 15: 1264-1276Crossref PubMed Scopus (53) Google SIK1 mRNA was present in adrenal and in in and skeletal in the The high expression of in adipose tissues to the level of SIK2 mRNA during the process of preadipocyte-adipocyte differentiation. 3T3-L1 were for in to they were treated with the differentiation to the differentiation. several time the the cells were to mRNA of SIK2 and several other differentiation in SIK2 mRNA was expressed the first and the level high the were mostly adipocytes by data the other the level of SIK1 although with that of SIK2 the in in the seemed to a during the first and at the elevated level The level of a of C.M. H.S. Cell. Full Text PDF PubMed Scopus Google to the The mRNA of c/EBPβ and to early in the differentiation Z. M. PubMed Scopus Google during the first in a similar to that of SIK2. The mRNA of of such as and J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google A. Friedman J.M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google to 2 We further examined the expression of during the first the stimulation The SIK2 mRNA level within 1 the stimulation, and the almost with that of c/EBPβ mRNA. The of mRNA level within 1 as the level gradually a to in the of cAMP, and was to the of the were for 2 with a hormone a of the and the mRNA were examined The of gene seemed to activated by to the similar degree as by the mixture, although insulin could also the The suggest that SIK2 involved in the signal in adipose tissues. could to we could the intracellular of SIK2 to for the we noticed that several serine/threonine to SIK2 protein kinase, and kinase, are to in the (6White M.F. Diabetologia. 1997; 40 Suppl. 2: 2-17Crossref PubMed Scopus (465) Google Scholar, 7Saltiel A.R. Cell. 2001; 104: 517-529Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar). we that the of SIK2 might found in the insulin-stimulated signaling of adipose tissues. in kinase suggest that the phosphorylation of SIK is is the and and are and H. and M. a in human IRS-1 seemed with the we first several similar to could as of SIK2. in a was and the was phosphorylated by SIK2. the IRS-1 serine we that of the in the might phosphorylated by SIK2. that in an equivalent for human was a for phosphorylation by human IRS-1 its was coexpressed with SIK2 SIK2 in COS-7 in the of the IRS-1 was phosphorylated in the cells, although a phosphorylated IRS-1 was found in the cells, that IRS-1 could also phosphorylated in COS-7 cells by a protein other than SIK2. the IRS-1 could at phosphorylated in the the that Ser794 in human IRS-1 could phosphorylated by SIK2 in the that the phosphorylated in human IRS-1 was we the by a the phosphorylated IRS-1 of The phosphorylated Ser794 was in the from the and the A very was in the of the from the and the the cells a serine other than SIK2 that could phosphorylate Ser794. the could the phosphorylation in the from the and SIK2 phosphorylates the in mouse adipose cells could by SIK2 in 3T3-L1 in to the phosphorylation by the from the adipocytes rather than preadipocytes, the level of IRS-1 protein in the is rather the other the of adipocytes by would rather we to an for the SIK2 expression in When of for SIK2 were to the 3T3-L1 cells for proteins by the in the in the The of IRS-1 present in the was by SIK2 overexpression in When the were carried out by in the molecular of IRS-1 in the from the adipocytes in from the control cells the The that the SIK2 the could phosphorylate of IRS-1 to the IRS-1 could the and the of the human IRS-1 its phosphorylation was coexpressed in the assay The activated activity was further elevated in the presence of human IRS-1. seemed to in the presence of that IRS-1 was phosphorylated at the and the phosphorylated IRS-1 could the a kinase of phosphorylation was the expressed SIK2 was in When the was in the activated activity was completely in the presence the of that the of SIK2 to repress the might the of IRS-1. The phosphorylation of in IRS-1 by has been reported to in in to N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) reported that the could phosphorylated in the of diabetic rats by a serine kinase that was different from These to the level of SIK2 in tissues of diabetic mice. white adipose brown adipose liver, and skeletal were from mice (30Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2112) Google Scholar) the mice and that SIK2 mRNA was present in the white as as brown adipose tissues of diabetic and animals at the similar the SIK2 mRNA in and skeletal were with in the adipose tissues. seemed to in the mRNA in tissues between diabetic and animals. to the of SIK1 mRNA in brown adipose liver, and skeletal of diabetic mice were elevated with of mice. of the tissues were to an the COOH-terminal of SIK2. The were to by the the The results that the content of SIK2 protein in white adipose tissue of diabetic animals was than that of animals. The SIK2 content in brown adipose tissue of diabetic on the other was than that of animals. the SIK2 in and skeletal were the were in tissues, between the diabetic and animals. The was for protein kinase activity as a in the of white adipose tissue of diabetic mice SIK2 kinase activity than that of the animals. the from brown adipose tissue of diabetic mice SIK2 kinase activity than that of animals. These results seemed with the in SIK2 protein content between the two animals The SIK2 activity and that from diabetic animals a activity than that from the animals. The of skeletal from diabetic animals SIK2 whereas that from animals results suggest that SIK2 protein as as its activity were elevated in the white adipose tissue of diabetic mice. We for the first time the properties of SIK2. they are similar to of SIK1. several properties different between the two kinases SIK1 was found in the of cells, SIK2, as by green signal of the expressed was mostly present in the of 3T3-L1 the presence of a of SIK2 in the could the could the intracellular of the expressed The of SIK2, in the by a highly SIK2. SIK2 could repress the of gene the presence of SIK2. repression by the that SIK2 could as a for the gene transcription, as was the with SIK1 H. Katoh Y. Horike N. Doi J. Okamoto M. J. Biol. Chem. 2002; 277: 42334-42343Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The expression of gene in the adipose tissues and its in the signal SIK2 to of the very early during preadipocyte-adipocyte differentiation. The of SIK2 mRNA level almost with that of the such as c/EBPβ and The by SIK2 during the initial stage of differentiation has to it that the overexpression of SIK2 could repress the on on SIK1 J. Takemori H. M. Nonaka Y. Okamoto M. J. Endocrinol. 2001; PubMed Scopus Google SIK2 is to repress the activity of and the other the of signaling has been reported Mol. Cell. Biol. PubMed Scopus Google Scholar, N. J. J. K. A. Mol. Endocrinol. 2001; 15: Google Scholar) to an of differentiation. When the was by by of the of 3T3-L1 cells was Mol. Cell. Biol. PubMed Scopus Google Scholar). The overexpression of in 3T3-L1 cells the action of J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) and induced the A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). These suggest that SIK2 might involved in the of the of for the of a that SIK2 also in the by the signal occurring in the early stage of as suggest the by serine/threonine in the insulin signaling (6White M.F. Diabetologia. 1997; 40 Suppl. 2: 2-17Crossref PubMed Scopus (465) Google Scholar, 7Saltiel A.R. Cell. 2001; 104: 517-529Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar). Several serine protein kinase, kinase H. A. 1997; PubMed Scopus Google kinase R.S. M.F. J. Biol. Chem. Full Text PDF PubMed Google Chen J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google J. K. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. K. J.M. M. Mol. Endocrinol. PubMed Scopus Google Scholar, H. A. 2001; PubMed Scopus Google kinase L. Shulman G.I. Lee A. A. A. M.F. J. 2001; PubMed Scopus Google Scholar, Yenush L. R. M.F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google J. K. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google are to phosphorylate IRS-1. The of in mouse in phosphorylation of in IRS-1 N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The IRS-1 was also to The IRS-1 a high to and activated the such as N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the tyrosine phosphorylation of IRS-1 and the of the signaling are to the insulin and the resistance to a high level of glucose (3Zick Y. Trends Cell Biol. 2001; 11: 437-441Abstract Full Text PDF PubMed Scopus (186) Google Scholar). in the of high type 2 diabetic the similar of insulin signaling IRS-1 and in the serine phosphorylation of IRS-1 was to eventually the insulin resistance M. M. A. Y. H. K. M. Y. Y. M. Y. 1999; PubMed Scopus Google Scholar, K. Y. N. H. M. Y. M. H. N. K. Y. M. 2001; PubMed Scopus Google Scholar). R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) reported the presence in the of a diabetic of a kinase responsible for the phosphorylation of was from we that SIK2 might involved in the serine phosphorylation of insulin-signaling and the signaling in adipose tissues. We found that Ser794 in human an equivalent of in could phosphorylated by SIK2 in the in kinase as as in COS-7 cells 3T3-L1 we SIK2 was activated in tissues from diabetic animals. SIK2 was found activated in the white adipose tissue of diabetic mice. SIK2, by in might involved in of insulin of white adipose tissues of diabetic mice. The was different for the of diabetic SIK2 level seemed similar to that of animals. the of SIK1 mRNA were found elevated in the brown adipose tissues, and skeletal of diabetic animals. with SIK2 we could the content and activity of SIK1 protein in tissues. a that was as Z. Takemori H. Halder S.K. Nonaka Y. Okamoto M. FEBS Lett. 1999; 453: 135-139Crossref PubMed Scopus (119) Google might the kinase responsible for phosphorylation of in IRS-1 in the of diabetic animals. we here that in the diabetic SIK2 in white adipose tissues and SIK1 in brown adipose tissues, and skeletal might involved in the of the insulin signaling occurring in tissues and might in the of type 2 We are to Lee A. Medical for