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 25-MAY-2022, entry version 141. 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; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC 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 receptor RT substrate-1, and activation in diabetic animals of salt-inducible kinase- RT 2."; RL J. Biol. Chem. 278:18440-18447(2003). RN [2] RP FUNCTION, ACTIVITY REGULATION, PHOSPHORYLATION AT THR-175 AND SER-587, AND RP 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 LKB1- RT SIK signaling cascade."; RL FEBS J. 273:2730-2748(2006). RN [3] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-532; SER-534 AND SER-587, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 expression."; RL Cell 143:1174-1189(2010). RN [4] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH 14-3-3 RP PROTEINS, MUTAGENESIS OF THR-175; SER-343; SER-358; THR-484; SER-587 AND RP 595-THR--MET-624, AND PHOSPHORYLATION AT SER-358 AND 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. 285:467-480(2018). RN [5] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=34732767; DOI=10.1038/s41598-021-00986-0; RA Nefla M., Darling N.J., van Gijsel Bonnello M., Cohen P., Arthur J.S.C.; RT "Salt inducible kinases 2 and 3 are required for thymic T cell RT development."; RL Sci. Rep. 11:21550-21550(2021). CC -!- FUNCTION: Serine/threonine-protein kinase that plays a role in many CC biological processes such as fatty acid oxidation, autophagy, immune CC response or glucose metabolism (PubMed:12624099, PubMed:16817901, CC PubMed:29211348). Phosphorylates 'Ser-794' of IRS1 in insulin- CC stimulated adipocytes, potentially modulating the efficiency of insulin CC signal transduction (PubMed:12624099). Inhibits CREB activity by CC phosphorylating and repressing TORCs, the CREB-specific coactivators CC (PubMed:16817901). Phosphorylates EP300 and thus inhibits its histone CC acetyltransferase activity. In turn, regulates the DNA-binding ability CC of several transcription factors such as PPARA or MLXIPL (By CC similarity). Plays also a role in thymic T-cell development CC (PubMed:34732767). {ECO:0000250|UniProtKB:Q9H0K1, CC ECO:0000269|PubMed:12624099, ECO:0000269|PubMed:16817901, CC ECO:0000269|PubMed:29211348, ECO:0000269|PubMed:34732767}. 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, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:12624099, 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, Thr-484 CC and/or Ser-587, probably by PKA, which triggers interaction with 14-3-3 CC proteins (PubMed:29211348). {ECO:0000250|UniProtKB:Q9H0K1, CC ECO:0000269|PubMed:29211348}. CC -!- SUBUNIT: Interacts with and phosphorylates TORC2/CRTC2 CC (PubMed:29211348). Interacts (when phosphorylated at Ser-343, Ser-358, CC Thr-484 and/or Ser-587) with 14-3-3 proteins; the interaction inhibits CC its kinase activity towards TORCs (PubMed:29211348). There is a CC cooperative effect of the phosphorylation sites in 14-3-3 binding as CC the interaction is stronger when more sites are modified. CC {ECO:0000269|PubMed:29211348}. CC -!- INTERACTION: CC Q8CFH6; 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 tissues CC with levels increasing during adipocyte differentiation. Lower levels CC observed in the testis. {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 STE20- CC related adapter-alpha (STRADA) pseudo kinase and CAB39 (By similarity). CC Phosphorylated at Thr-484 in response to insulin in adipocytes (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 thus CC inactivation (PubMed:29211348). {ECO:0000250|UniProtKB:Q9H0K1, CC ECO:0000269|PubMed:29211348}. CC -!- PTM: Acetylation at Lys-53 inhibits kinase activity. Deacetylated by CC HDAC6 (By similarity). {ECO:0000250|UniProtKB:Q9H0K1}. CC -!- DISRUPTION PHENOTYPE: Constitutive knockout combined with conditional CC knockout of SIK3 in the haemopoietic cells results in a severe CC reduction in peripheral T-cells without reducing B-cell number. CC {ECO:0000269|PubMed:34732767}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr CC 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 AlphaFoldDB; Q8CFH6; -. DR SMR; Q8CFH6; -. DR BioGRID; 231647; 3. DR DIP; DIP-60734N; -. DR IntAct; Q8CFH6; 1. DR STRING; 10090.ENSMUSP00000038761; -. DR iPTMnet; Q8CFH6; -. DR PhosphoSitePlus; Q8CFH6; -. DR jPOST; Q8CFH6; -. DR MaxQB; Q8CFH6; -. DR PaxDb; Q8CFH6; -. DR PRIDE; Q8CFH6; -. DR ProteomicsDB; 261363; -. DR DNASU; 235344; -. DR GeneID; 235344; -. DR KEGG; mmu:235344; -. DR CTD; 23235; -. DR MGI; MGI:2445031; Sik2. DR eggNOG; KOG0586; Eukaryota. DR InParanoid; Q8CFH6; -. DR OrthoDB; 1127668at2759; -. DR PhylomeDB; Q8CFH6; -. DR BioGRID-ORCS; 235344; 4 hits in 77 CRISPR screens. DR ChiTaRS; Sik2; mouse. DR PRO; PR:Q8CFH6; -. DR Proteomes; UP000000589; Unplaced. DR RNAct; Q8CFH6; protein. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. 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:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:RHEA. 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: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; Cytoplasm; Kinase; Magnesium; Metal-binding; KW Nucleotide-binding; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase. FT CHAIN 1..931 FT /note="Serine/threonine-protein kinase SIK2" FT /id="PRO_0000086663" FT DOMAIN 20..271 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 295..335 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT NP_BIND 26..34 FT /note="ATP" FT /evidence="ECO:0000250|UniProtKB:Q13131, FT ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 565..586 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 595..624 FT /note="RK-rich region; required for cAMP responsiveness" FT /evidence="ECO:0000269|PubMed:29211348" FT REGION 631..662 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 744..768 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 798..842 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 801..838 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 142 FT /note="Proton acceptor" FT /evidence="ECO:0000250|UniProtKB:Q13131, FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10027" FT BINDING 49 FT /note="ATP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000269|PubMed:12624099" FT MOD_RES 25 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9H0K1" FT MOD_RES 53 FT /note="N6-acetyllysine; by EP300" FT /evidence="ECO:0000250|UniProtKB:Q9H0K1" FT MOD_RES 175 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:16817901" FT MOD_RES 358 FT /note="Phosphoserine" FT /evidence="ECO:0000305|PubMed:29211348" FT MOD_RES 484 FT /note="Phosphothreonine" FT /evidence="ECO:0000305|PubMed:29211348" FT MOD_RES 532 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 534 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 587 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MUTAGEN 49 FT /note="K->M: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:12624099, FT ECO:0000269|PubMed:16817901" FT MUTAGEN 175 FT /note="T->A: Reduced inhibitory activity towards TORCs in FT presence and absence of cAMP signaling." FT /evidence="ECO:0000269|PubMed:16817901" FT MUTAGEN 175 FT /note="T->E: Low levels of constitutive activity." FT /evidence="ECO:0000269|PubMed:16817901" FT MUTAGEN 343 FT /note="S->A: Reduced interaction with 14-3-3 proteins in FT response to cAMP signaling and, thus, still able to inhibit FT TORC activity." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 358 FT /note="S->A: Reduced interaction with 14-3-3 proteins in FT response to cAMP signaling and, thus, still able to inhibit FT TORC activity. Resistant to inhibition by cAMP signaling FT and, thus, still able to inhibit TORC activity; when FT associated with A-484 and A-587." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 484 FT /note="T->A: Reduced interaction with 14-3-3 proteins in FT response to cAMP signaling and, thus, still able to inhibit FT TORC activity. Resistant to inhibition by cAMP signaling FT and, thus, still able to inhibit TORC activity; when FT associated with A-358 and A-587." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 587 FT /note="S->A: Reduced interaction with 14-3-3 proteins in FT response to cAMP signaling and, thus, still able to inhibit FT TORC activity. Resistant to inhibition by cAMP signaling FT and, thus, still able to inhibit TORC activity; when FT associated with A-358 and A-484." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 595..624 FT /note="Missing: Reduced 14-3-3 interaction. Reduced FT inactivation following cAMP signaling." FT /evidence="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 //