ID SIK2_MOUSE Reviewed; 931 AA. AC Q8CFH6; DT 15-FEB-2005, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 05-DEC-2018, entry version 124. DE RecName: Full=Serine/threonine-protein kinase SIK2; DE EC=2.7.11.1 {ECO:0000269|PubMed:12624099, ECO:0000269|PubMed:29211348}; DE AltName: Full=Salt-inducible kinase 2; DE Short=SIK-2; DE AltName: Full=Serine/threonine-protein kinase SNF1-like kinase 2; GN Name=Sik2; Synonyms=Snf1lk2; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; OC Muroidea; Muridae; Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] {ECO:0000305, ECO:0000312|EMBL:BAC53845.1} RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MUTAGENESIS OF LYS-49. RC TISSUE=Adipose tissue {ECO:0000312|EMBL:BAC53845.1}; RX PubMed=12624099; DOI=10.1074/jbc.M211770200; RA Horike N., Takemori H., Katoh Y., Doi J., Min L., Asano T., Sun X.J., RA Yamamoto H., Kasayama S., Muraoka M., Nonaka Y., Okamoto M.; RT "Adipose-specific expression, phosphorylation of Ser794 in insulin RT receptor substrate-1, and activation in diabetic animals of salt- RT inducible kinase-2."; RL J. Biol. Chem. 278:18440-18447(2003). RN [2] RP FUNCTION, ACTIVITY REGULATION, PHOSPHORYLATION AT THR-175 AND SER-587, RP AND MUTAGENESIS OF LYS-49 AND THR-175. RX PubMed=16817901; DOI=10.1111/j.1742-4658.2006.05291.x; RA Katoh Y., Takemori H., Lin X.-Z., Tamura M., Muraoka M., Satoh T., RA Tsuchiya Y., Min L., Doi J., Miyauchi A., Witters L.A., Nakamura H., RA Okamoto M.; RT "Silencing the constitutive active transcription factor CREB by the RT LKB1-SIK signaling cascade."; RL FEBS J. 273:2730-2748(2006). RN [3] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-532; SER-534 AND RP SER-587, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas, and RC Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and RT expression."; RL Cell 143:1174-1189(2010). RN [4] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH RP 14-3-3 PROTEINS, MUTAGENESIS OF THR-175; SER-343; SER-358; THR-484; RP SER-587 AND 595-THR--MET-624, AND PHOSPHORYLATION AT SER-358 AND RP THR-484. RX PubMed=29211348; DOI=10.1111/febs.14351; RA Sonntag T., Vaughan J.M., Montminy M.; RT "14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible RT kinases (SIKs)."; RL FEBS J. 0:0-0(2017). CC -!- FUNCTION: Phosphorylates 'Ser-789' of IRS1 in insulin-stimulated CC adipocytes, potentially modulating the efficiency of insulin CC signal transduction. Inhibits CREB activity by phosphorylating and CC inhibiting activity of TORCs, the CREB-specific coactivators, like CC CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signaling CC (PubMed:29211348). {ECO:0000269|PubMed:12624099, CC ECO:0000269|PubMed:16817901, ECO:0000269|PubMed:29211348}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:12624099, CC ECO:0000269|PubMed:29211348}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:12624099, CC ECO:0000269|PubMed:29211348}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:12624099}; CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-175 (By CC similarity). Inhibited by phosphorylation at Ser-343, Ser-358, CC Thr-484 and/or Ser-587, probably by PKA, which triggers CC interaction with 14-3-3 proteins (PubMed:29211348). CC {ECO:0000250|UniProtKB:Q9H0K1, ECO:0000269|PubMed:29211348}. CC -!- SUBUNIT: Interacts with and phosphorylates TORC2/CRTC2 CC (PubMed:29211348). Interacts (when phosphorylated at Ser-343, Ser- CC 358, Thr-484 and/or Ser-587) with 14-3-3 proteins; the interaction CC inhibits its kinase activity towards TORCs (PubMed:29211348). CC There is a cooperative effect of the phosphorylation sites in 14- CC 3-3 binding as the interaction is stronger when more sites are CC modified. {ECO:0000269|PubMed:29211348}. CC -!- INTERACTION: CC P61809:Cdk5r1; NbExp=3; IntAct=EBI-16094102, EBI-7840438; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12624099}. CC -!- TISSUE SPECIFICITY: Present in both white and brown adipose CC tissues with levels increasing during adipocyte differentiation. CC Lower levels observed in the testis. CC {ECO:0000269|PubMed:12624099}. CC -!- DOMAIN: The RK-rich region is required for cAMP responsiveness. CC {ECO:0000269|PubMed:29211348}. CC -!- PTM: Phosphorylated at Thr-175 by STK11/LKB1 in complex with CC STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39 (By CC similarity). Phosphorylation at Ser-358, Thr-484 and/or Ser-587 CC following cAMP signaling is required for 14-3-3 interaction and CC thus inactivation (PubMed:29211348). CC {ECO:0000250|UniProtKB:Q9H0K1, ECO:0000269|PubMed:29211348}. CC -!- PTM: Acetylation at Lys-53 inhibits kinase activity. Deacetylated CC by HDAC6 (By similarity). {ECO:0000250|UniProtKB:Q9H0K1}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK CC Ser/Thr protein kinase family. SNF1 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB067780; BAC53845.1; -; mRNA. DR CCDS; CCDS40627.1; -. DR RefSeq; NP_848825.2; NM_178710.3. DR UniGene; Mm.104932; -. DR UniGene; Mm.439989; -. DR ProteinModelPortal; Q8CFH6; -. DR SMR; Q8CFH6; -. DR BioGrid; 231647; 1. DR DIP; DIP-60734N; -. DR IntAct; Q8CFH6; 1. DR STRING; 10090.ENSMUSP00000038761; -. DR iPTMnet; Q8CFH6; -. DR PhosphoSitePlus; Q8CFH6; -. DR MaxQB; Q8CFH6; -. DR PaxDb; Q8CFH6; -. DR PRIDE; Q8CFH6; -. DR DNASU; 235344; -. DR GeneID; 235344; -. DR KEGG; mmu:235344; -. DR CTD; 23235; -. DR MGI; MGI:2445031; Sik2. DR eggNOG; KOG0586; Eukaryota. DR eggNOG; ENOG410XNQ0; LUCA. DR HOGENOM; HOG000048716; -. DR InParanoid; Q8CFH6; -. DR KO; K16311; -. DR PhylomeDB; Q8CFH6; -. DR PRO; PR:Q8CFH6; -. DR Proteomes; UP000000589; Unplaced. DR CleanEx; MM_SNF1LK2; -. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0031588; C:nucleotide-activated protein kinase complex; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; IDA:MGI. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0042149; P:cellular response to glucose starvation; IBA:GO_Central. DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:MGI. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0032007; P:negative regulation of TOR signaling; IBA:GO_Central. DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0046626; P:regulation of insulin receptor signaling pathway; IDA:UniProtKB. DR CDD; cd14071; STKc_SIK; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR017090; Ser/Thr_kinase_SIK1/2. DR InterPro; IPR034672; SIK. DR InterPro; IPR015940; UBA. DR Pfam; PF00069; Pkinase; 1. DR PIRSF; PIRSF037014; Ser/Thr_PK_SNF1-like; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS50030; UBA; 1. PE 1: Evidence at protein level; KW Acetylation; ATP-binding; Complete proteome; Cytoplasm; Kinase; KW Magnesium; Metal-binding; Nucleotide-binding; Phosphoprotein; KW Reference proteome; Serine/threonine-protein kinase; Transferase. FT CHAIN 1 931 Serine/threonine-protein kinase SIK2. FT /FTId=PRO_0000086663. FT DOMAIN 20 271 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT DOMAIN 295 335 UBA. {ECO:0000255|PROSITE- FT ProRule:PRU00212}. FT NP_BIND 26 34 ATP. {ECO:0000250|UniProtKB:Q13131, FT ECO:0000255|PROSITE-ProRule:PRU00159}. FT REGION 595 624 RK-rich region; required for cAMP FT responsiveness. FT {ECO:0000269|PubMed:29211348}. FT ACT_SITE 142 142 Proton acceptor. FT {ECO:0000250|UniProtKB:Q13131, FT ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027}. FT BINDING 49 49 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159, FT ECO:0000269|PubMed:12624099}. FT MOD_RES 25 25 Phosphothreonine. FT {ECO:0000250|UniProtKB:Q9H0K1}. FT MOD_RES 53 53 N6-acetyllysine; by EP300. FT {ECO:0000250|UniProtKB:Q9H0K1}. FT MOD_RES 175 175 Phosphothreonine. FT {ECO:0000269|PubMed:16817901}. FT MOD_RES 358 358 Phosphoserine. FT {ECO:0000305|PubMed:29211348}. FT MOD_RES 484 484 Phosphothreonine. FT {ECO:0000305|PubMed:29211348}. FT MOD_RES 532 532 Phosphoserine. FT {ECO:0000244|PubMed:21183079}. FT MOD_RES 534 534 Phosphoserine. FT {ECO:0000244|PubMed:21183079}. FT MOD_RES 587 587 Phosphoserine. FT {ECO:0000244|PubMed:21183079}. FT MUTAGEN 49 49 K->M: Loss of kinase activity. FT {ECO:0000269|PubMed:12624099, FT ECO:0000269|PubMed:16817901}. FT MUTAGEN 175 175 T->A: Reduced inhibitory activity towards FT TORCs in presence and absence of cAMP FT signaling. {ECO:0000269|PubMed:16817901}. FT MUTAGEN 175 175 T->E: Low levels of constitutive FT activity. {ECO:0000269|PubMed:16817901}. FT MUTAGEN 343 343 S->A: Reduced interaction with 14-3-3 FT proteins in response to cAMP signaling FT and, thus, still able to inhibit TORC FT activity. {ECO:0000269|PubMed:29211348}. FT MUTAGEN 358 358 S->A: Reduced interaction with 14-3-3 FT proteins in response to cAMP signaling FT and, thus, still able to inhibit TORC FT activity. Resistant to inhibition by cAMP FT signaling and, thus, still able to FT inhibit TORC activity; when associated FT with A-484 and A-587. FT {ECO:0000269|PubMed:29211348}. FT MUTAGEN 484 484 T->A: Reduced interaction with 14-3-3 FT proteins in response to cAMP signaling FT and, thus, still able to inhibit TORC FT activity. Resistant to inhibition by cAMP FT signaling and, thus, still able to FT inhibit TORC activity; when associated FT with A-358 and A-587. FT {ECO:0000269|PubMed:29211348}. FT MUTAGEN 587 587 S->A: Reduced interaction with 14-3-3 FT proteins in response to cAMP signaling FT and, thus, still able to inhibit TORC FT activity. Resistant to inhibition by cAMP FT signaling and, thus, still able to FT inhibit TORC activity; when associated FT with A-358 and A-484. FT {ECO:0000269|PubMed:29211348}. FT MUTAGEN 595 624 Missing: Reduced 14-3-3 interaction. FT Reduced inactivation following cAMP FT signaling. {ECO:0000269|PubMed:29211348}. SQ SEQUENCE 931 AA; 104198 MW; 5CF2FB8DCDC689F4 CRC64; MVMADGPRHL QRGPVRVGFY DIEGTLGKGN FAVVKLGRHR TTKTEVAIKI IDKSQLDAVN LEKIYREVQI MKMLDHPHII KLYQVMETKS MLYLVTEYAK NGEIFDYLAN HGRLNESEAR RKFWQILSAV DYCHGRKVVH RDLKAENLLL DNNMNIKIAD FGFGNFFKTG ELLATWCGSP PYAAPEVFEG QQYEGPQLDI WSMGVVLYVL VCGALPFDGP TLPILRQRVL EGRFRIPYFM SEDCEHLIRR MLVLDPSKRL SIAQIKEHKW MLIEVPVQRP ILYPQEQENE PSIGEFNEQV LRLMHSLGID QQKTVESLQN KSYNHFAAIY FLLVERLKSH RSSFPVEQRL DGRQRRPSTI AEQTVAKAQT VGLPVTLHPP NVRLMRSTLL PQASNVEAFS FPTSSCQAEA AFMEEECVDT PKVNGCLLDP VPPVLVRKGC QSLPSSMMET SIDEGLETEG EAEEDPSQAF EAFQATRSGQ RRHTLSEVTN QLVVMPGAGK MFSMSDNPSL ESVDSEYDMG SAQRDLNFLE DSPSLKDIML ANQPSPRMTS PFISLRPANP AMQALSSQKR EAHNRSPVSF REGRRASDTS LTQGIVAFRQ HLQNLARTKG ILELNKVQLL YEQMGSNADP TLTSTAPQLQ DLSSSCPQEE ISQQQESVSS LSASMHPQLS PQQSLETQYL QHRLQKPNLL PKAQSPCPVY CKEPPRSLEQ QLQEHRLQQK RLFLQKQSQL QAYFNQMQIA ESSYPGPSQQ LALPHQETPL TSQQPPSFSL TQALSPVLEP SSEQMQFSSF LSQYPEMQLQ PLPSTPGPRA PPPLPSQLQQ HQQPPPPPPP PPPQQPGAAP TSLQFSYQTC ELPSTTSSVP NYPASCHYPV DGAQQSNLTG ADCPRSSGLQ DTASSYDPLA LSELPGLFDC EMVEAVDPQH NGVVSCLARE T //