ID SIK1_HUMAN Reviewed; 783 AA. AC P57059; A6NC84; Q5R2V5; Q6ZNL8; Q86YJ2; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 15-FEB-2005, sequence version 2. DT 27-MAR-2024, entry version 211. DE RecName: Full=Serine/threonine-protein kinase SIK1; DE EC=2.7.11.1 {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:29211348}; DE AltName: Full=Salt-inducible kinase 1; DE Short=SIK-1; DE AltName: Full=Serine/threonine-protein kinase SNF1-like kinase 1; DE Short=Serine/threonine-protein kinase SNF1LK; GN Name=SIK1; Synonyms=SIK, SNF1LK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, ACTIVITY RP REGULATION, PHOSPHORYLATION AT THR-182, AND MUTAGENESIS OF THR-182. RX PubMed=14976552; DOI=10.1038/sj.emboj.7600110; RA Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A., Boudeau J., RA Hawley S.A., Udd L., Maekelae T.P., Hardie D.G., Alessi D.R.; RT "LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, RT including MARK/PAR-1."; RL EMBO J. 23:833-843(2004). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Fetal lung; RA Shimizu N., Kudoh J., Shibuya K.; RL Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=10830953; DOI=10.1038/35012518; RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U., RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.; RT "The DNA sequence of human chromosome 21."; RL Nature 405:311-319(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-615. RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 20-783, AND VARIANT VAL-615. RC TISSUE=Spleen; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH YWHAZ. RX PubMed=16306228; DOI=10.1242/jcs.02670; RA Al-Hakim A.K., Goransson O., Deak M., Toth R., Campbell D.G., Morrice N.A., RA Prescott A.R., Alessi D.R.; RT "14-3-3 cooperates with LKB1 to regulate the activity and localization of RT QSK and SIK."; RL J. Cell Sci. 118:5661-5673(2005). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT RP THR-182 AND SER-186, INTERACTION WITH YWHAZ, AND MUTAGENESIS OF LYS-56; RP SER-135; SER-186; SER-209 AND SER-248. RX PubMed=18348280; DOI=10.1002/jcb.21737; RA Hashimoto Y.K., Satoh T., Okamoto M., Takemori H.; RT "Importance of autophosphorylation at Ser186 in the A-loop of salt RT inducible kinase 1 for its sustained kinase activity."; RL J. Cell. Biochem. 104:1724-1739(2008). RN [8] RP FUNCTION, AND MUTAGENESIS OF LYS-56. RX PubMed=19622832; DOI=10.1126/scisignal.2000369; RA Cheng H., Liu P., Wang Z.C., Zou L., Santiago S., Garbitt V., Gjoerup O.V., RA Iglehart J.D., Miron A., Richardson A.L., Hahn W.C., Zhao J.J.; RT "SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis."; RL Sci. Signal. 2:RA35-RA35(2009). RN [9] RP INVOLVEMENT IN DEE30, VARIANTS DEE30 THR-287; CYS-411 AND SER-636, AND RP CHARACTERIZATION OF VARIANTS DEE30 THR-287; CYS-411 AND SER-636. RX PubMed=25839329; DOI=10.1016/j.ajhg.2015.02.013; RA Hansen J., Snow C., Tuttle E., Ghoneim D.H., Yang C.S., Spencer A., RA Gunter S.A., Smyser C.D., Gurnett C.A., Shinawi M., Dobyns W.B., RA Wheless J., Halterman M.W., Jansen L.A., Paschal B.M., Paciorkowski A.R.; RT "De novo mutations in SIK1 cause a spectrum of developmental epilepsies."; RL Am. J. Hum. Genet. 96:682-690(2015). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH 14-3-3 RP PROTEINS, SUBCELLULAR LOCATION, DOMAIN, PTM, MUTAGENESIS OF THR-182; RP THR-473 AND SER-575, AND PHOSPHORYLATION AT THR-473 AND SER-575. 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 [11] RP VARIANTS [LARGE SCALE ANALYSIS] SER-15; ASN-142; SER-211; ASP-469; VAL-615; RP LEU-696 AND VAL-725. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Serine/threonine-protein kinase involved in various processes CC such as cell cycle regulation, gluconeogenesis and lipogenesis CC regulation, muscle growth and differentiation and tumor suppression. CC Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1. Inhibits CREB CC activity by phosphorylating and inhibiting activity of TORCs, the CREB- CC specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to CC cAMP signaling (PubMed:29211348). Acts as a tumor suppressor and plays CC a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered CC by cell detachment: required for phosphorylation of p53/TP53 in CC response to loss of adhesion and is able to suppress metastasis. Part CC of a sodium-sensing signaling network, probably by mediating CC phosphorylation of PPME1: following increases in intracellular sodium, CC SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein CC phosphatase 2A (PP2A), leading to dephosphorylation of CC sodium/potassium-transporting ATPase ATP1A1 and subsequent increase CC activity of ATP1A1. Acts as a regulator of muscle cells by CC phosphorylating and inhibiting class II histone deacetylases HDAC4 and CC HDAC5, leading to promote expression of MEF2 target genes in myocytes. CC Also required during cardiomyogenesis by regulating the exit of CC cardiomyoblasts from the cell cycle via down-regulation of CC CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by CC phosphorylating and repressing the CREB-specific coactivators CC CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also CC regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. CC In concert with CRTC1/TORC1, regulates the light-induced entrainment of CC the circadian clock by attenuating PER1 induction; represses CREB- CC mediated transcription of PER1 by phosphorylating and deactivating CC CRTC1/TORC1 (By similarity). {ECO:0000250|UniProtKB:Q60670, CC ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:16306228, CC ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:19622832, CC 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, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:18348280, 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:14976552, CC ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:29211348}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250}; CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-182 CC (PubMed:14976552). Also activated by phosphorylation on Thr-322 in CC response to increases in intracellular sodium in parallel with CC elevations in intracellular calcium through the reversible CC sodium/calcium exchanger (PubMed:14976552). Inhibited by CC phosphorylation at Thr-473 and Ser-575, probably by PKA, which triggers CC interaction with 14-3-3 proteins (PubMed:29211348). CC {ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:29211348}. CC -!- SUBUNIT: Interacts with ATP1A1 (By similarity). Interacts (when CC phosphorylated on Thr-182 and Ser-186) with YWHAZ (PubMed:16306228). CC Interacts (when phosphorylated at Thr-473 and/or Ser-575) with 14-3-3 CC proteins; the interaction inhibits kinase activity towards TORCs CC (PubMed:29211348). There is a cooperative effect of the phosphorylation CC sites in 14-3-3 binding as the interaction is stronger when both Thr- CC 473 and Ser-575 are modified (PubMed:29211348). CC {ECO:0000250|UniProtKB:Q9R1U5, ECO:0000269|PubMed:16306228, CC ECO:0000269|PubMed:18348280}. CC -!- INTERACTION: CC P57059; P62258: YWHAE; NbExp=4; IntAct=EBI-1181640, EBI-356498; CC P57059; P63104: YWHAZ; NbExp=5; IntAct=EBI-1181640, EBI-347088; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16306228, CC ECO:0000269|PubMed:29211348}. Nucleus {ECO:0000269|PubMed:16306228, CC ECO:0000269|PubMed:29211348}. Note=Locates to cytoplasm when inactive CC following cAMP-induced phosphorylation, probably by PKA CC (PubMed:29211348). CC -!- DOMAIN: The RK-rich region determines the subcellular location and is CC required for cAMP responsiveness. {ECO:0000305|PubMed:29211348}. CC -!- PTM: Phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20- CC related adapter-alpha (STRADA) pseudo kinase and CAB39, leading to its CC activation. Phosphorylation at Thr-182 promotes autophosphorylation at CC Ser-186, which is required for sustained activity. Autophosphorylation CC at Ser-186 is maintained by sequential phosphorylation at Thr-182 by CC GSK3-beta. GSK3-beta cannot initiate phosphorylation at Thr-182, it can CC only maintain it. Phosphorylation at Ser-575 in response to cAMP CC signaling promotes translocation to the cytoplasm (PubMed:29211348). CC Phosphorylation at Thr-322 by CaMK1 following intracellular sodium CC concentration leads to activation. {ECO:0000269|PubMed:14976552, CC ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:29211348}. CC -!- DISEASE: Developmental and epileptic encephalopathy 30 (DEE30) CC [MIM:616341]: A form of epileptic encephalopathy, a heterogeneous group CC of severe early-onset epilepsies characterized by refractory seizures, CC neurodevelopmental impairment, and poor prognosis. Development is CC normal prior to seizure onset, after which cognitive and motor delays CC become apparent. {ECO:0000269|PubMed:25839329}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Note=Defects in SIK1 may be associated with some cancers, such CC as breast cancers. Loss of SIK1 correlates with poor patient outcome in CC breast cancers (PubMed:19622832). {ECO:0000269|PubMed:19622832}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr CC protein kinase family. AMPK 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; AB047786; BAD74070.1; -; mRNA. DR EMBL; AP001751; BAA95536.1; -; Genomic_DNA. DR EMBL; BC038504; AAH38504.1; -; mRNA. DR EMBL; AK131076; BAC85126.1; -; mRNA. DR CCDS; CCDS33575.1; -. DR RefSeq; NP_001307572.1; NM_001320643.2. DR RefSeq; NP_775490.2; NM_173354.4. DR AlphaFoldDB; P57059; -. DR SMR; P57059; -. DR BioGRID; 127260; 57. DR BioGRID; 3195539; 6. DR IntAct; P57059; 29. DR MINT; P57059; -. DR STRING; 9606.ENSP00000270162; -. DR BindingDB; P57059; -. DR ChEMBL; CHEMBL6082; -. DR DrugBank; DB08912; Dabrafenib. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; P57059; -. DR GuidetoPHARMACOLOGY; 2197; -. DR TCDB; 8.A.104.1.14; the 5'-amp-activated protein kinase (ampk) family. DR GlyGen; P57059; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P57059; -. DR PhosphoSitePlus; P57059; -. DR BioMuta; SIK1; -. DR DMDM; 59803093; -. DR EPD; P57059; -. DR jPOST; P57059; -. DR MassIVE; P57059; -. DR MaxQB; P57059; -. DR PaxDb; 9606-ENSP00000270162; -. DR PeptideAtlas; P57059; -. DR ProteomicsDB; 56978; -. DR Antibodypedia; 9946; 386 antibodies from 36 providers. DR DNASU; 150094; -. DR Ensembl; ENST00000270162.8; ENSP00000270162.6; ENSG00000142178.9. DR GeneID; 102724428; -. DR GeneID; 150094; -. DR KEGG; hsa:102724428; -. DR KEGG; hsa:150094; -. DR MANE-Select; ENST00000270162.8; ENSP00000270162.6; NM_173354.5; NP_775490.2. DR UCSC; uc002zdf.4; human. DR AGR; HGNC:11142; -. DR CTD; 150094; -. DR DisGeNET; 102724428; -. DR DisGeNET; 150094; -. DR GeneCards; SIK1; -. DR HGNC; HGNC:11142; SIK1. DR HPA; ENSG00000142178; Low tissue specificity. DR MalaCards; SIK1; -. DR MIM; 605705; gene. DR MIM; 616341; phenotype. DR neXtProt; NX_P57059; -. DR OpenTargets; ENSG00000142178; -. DR Orphanet; 1934; Early infantile epileptic encephalopathy. DR Orphanet; 1935; Early myoclonic encephalopathy. DR Orphanet; 3451; Infantile spasms syndrome. DR PharmGKB; PA164725717; -. DR VEuPathDB; HostDB:ENSG00000142178; -. DR eggNOG; KOG0586; Eukaryota. DR GeneTree; ENSGT00940000154989; -. DR HOGENOM; CLU_000288_87_2_1; -. DR InParanoid; P57059; -. DR OMA; IAQIWQH; -. DR OrthoDB; 5475340at2759; -. DR PhylomeDB; P57059; -. DR TreeFam; TF315213; -. DR PathwayCommons; P57059; -. DR Reactome; R-HSA-400253; Circadian Clock. DR SignaLink; P57059; -. DR SIGNOR; P57059; -. DR BioGRID-ORCS; 102724428; 0 hits in 6 CRISPR screens. DR BioGRID-ORCS; 150094; 14 hits in 1186 CRISPR screens. DR ChiTaRS; SIK1; human. DR GeneWiki; SNF1LK; -. DR Pharos; P57059; Tchem. DR PRO; PR:P57059; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; P57059; Protein. DR Bgee; ENSG00000142178; Expressed in mucosa of stomach and 97 other cell types or tissues. DR ExpressionAtlas; P57059; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0071889; F:14-3-3 protein binding; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0008140; F:cAMP response element binding protein binding; ISS:UniProtKB. DR GO; GO:0042826; F:histone deacetylase binding; IEA:Ensembl. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI: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:0043276; P:anoikis; IEA:Ensembl. DR GO; GO:0055007; P:cardiac muscle cell differentiation; ISS:UniProtKB. DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW. DR GO; GO:0043153; P:entrainment of circadian clock by photoperiod; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0032792; P:negative regulation of CREB transcription factor activity; ISS:UniProtKB. DR GO; GO:0045721; P:negative regulation of gluconeogenesis; ISS:UniProtKB. DR GO; GO:0010868; P:negative regulation of triglyceride biosynthetic process; ISS:UniProtKB. DR GO; GO:2000210; P:positive regulation of anoikis; IMP:BHF-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0045595; P:regulation of cell differentiation; ISS:UniProtKB. DR GO; GO:0007346; P:regulation of mitotic cell cycle; ISS:UniProtKB. DR GO; GO:0010830; P:regulation of myotube differentiation; ISS:UniProtKB. DR GO; GO:0002028; P:regulation of sodium ion transport; ISS:UniProtKB. DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW. DR CDD; cd14071; STKc_SIK; 1. DR CDD; cd14408; UBA_SIK1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 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 PANTHER; PTHR24346; MAP/MICROTUBULE AFFINITY-REGULATING KINASE; 1. DR PANTHER; PTHR24346:SF47; NON-SPECIFIC SERINE_THREONINE PROTEIN KINASE-RELATED; 1. DR Pfam; PF00069; Pkinase; 1. DR PIRSF; PIRSF037014; Ser/Thr_PK_SNF1-like; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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. DR Genevisible; P57059; HS. PE 1: Evidence at protein level; KW ATP-binding; Biological rhythms; Cell cycle; Cytoplasm; KW Developmental protein; Differentiation; Disease variant; Epilepsy; Kinase; KW Magnesium; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein; KW Reference proteome; Serine/threonine-protein kinase; Transferase; KW Tumor suppressor. FT CHAIN 1..783 FT /note="Serine/threonine-protein kinase SIK1" FT /id="PRO_0000086659" FT DOMAIN 27..278 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 303..343 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT REGION 353..377 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 449..477 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 583..612 FT /note="RK-rich region; required for cAMP responsiveness and FT nuclear localization" FT /evidence="ECO:0000305|PubMed:29211348" FT REGION 619..643 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 457..477 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 149 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 33..41 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 56 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305" FT MOD_RES 182 FT /note="Phosphothreonine; by LKB1 and GSK3-beta" FT /evidence="ECO:0000269|PubMed:14976552, FT ECO:0000269|PubMed:18348280" FT MOD_RES 186 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:18348280" FT MOD_RES 322 FT /note="Phosphothreonine; by CaMK1" FT /evidence="ECO:0000250|UniProtKB:Q9R1U5" FT MOD_RES 473 FT /note="Phosphothreonine; by PKA" FT /evidence="ECO:0000305|PubMed:29211348" FT MOD_RES 575 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q60670, FT ECO:0000305|PubMed:29211348" FT VARIANT 15 FT /note="G -> S (in dbSNP:rs3746951)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041087" FT VARIANT 142 FT /note="D -> N (in dbSNP:rs45491503)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041088" FT VARIANT 211 FT /note="G -> S (in a glioblastoma multiforme sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041089" FT VARIANT 287 FT /note="P -> T (in DEE30; no change in subcellular location; FT dbSNP:rs786205159)" FT /evidence="ECO:0000269|PubMed:25839329" FT /id="VAR_073701" FT VARIANT 411 FT /note="S -> C (in DEE30; no change in subcellular FT location)" FT /evidence="ECO:0000269|PubMed:25839329" FT /id="VAR_073702" FT VARIANT 430 FT /note="R -> W (in dbSNP:rs34164089)" FT /id="VAR_033910" FT VARIANT 469 FT /note="G -> D (in a metastatic melanoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041090" FT VARIANT 615 FT /note="A -> V (in dbSNP:rs430554)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17344846" FT /id="VAR_021255" FT VARIANT 636 FT /note="G -> S (in DEE30; no change in subcellular location; FT dbSNP:rs786205163)" FT /evidence="ECO:0000269|PubMed:25839329" FT /id="VAR_073703" FT VARIANT 696 FT /note="P -> L (in dbSNP:rs56386767)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041091" FT VARIANT 725 FT /note="A -> V (in dbSNP:rs35596465)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041092" FT MUTAGEN 56 FT /note="K->M: Loss of kinase activity." FT /evidence="ECO:0000269|PubMed:18348280, FT ECO:0000269|PubMed:19622832" FT MUTAGEN 135 FT /note="S->A: Decreased kinase activity without affecting FT much autophosphorylation status." FT /evidence="ECO:0000269|PubMed:18348280" FT MUTAGEN 182 FT /note="T->A: Prevents phosphorylation and activation by FT STK11/LKB1 complex. Reduced inhibition of CRTC3-mediated FT transcriptional activity." FT /evidence="ECO:0000269|PubMed:14976552, FT ECO:0000269|PubMed:29211348" FT MUTAGEN 186 FT /note="S->A,D,C,G: Impaired autophosphorylation and kinase FT activity." FT /evidence="ECO:0000269|PubMed:18348280" FT MUTAGEN 186 FT /note="S->T: Does not autophosphorylation and kinase FT activity." FT /evidence="ECO:0000269|PubMed:18348280" FT MUTAGEN 209 FT /note="S->A: Decreased kinase activity without affecting FT much autophosphorylation status." FT /evidence="ECO:0000269|PubMed:18348280" FT MUTAGEN 248 FT /note="S->A: Decreased kinase activity without affecting FT much autophosphorylation status." FT /evidence="ECO:0000269|PubMed:18348280" FT MUTAGEN 473 FT /note="T->A: Reduced but still present interaction with FT 14-3-3 proteins in response to cAMP signaling and, thus, FT still able to inhibit TORC activity. Resistant to FT inhibition by cAMP signaling and, thus, still able to FT inhibit TORC activity; when associated with A-575." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 473 FT /note="T->E: Reduced but still present interaction with FT 14-3-3 proteins in response to cAMP signaling and, thus, FT still able to inhibit TORC activity." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 575 FT /note="S->A: Loss of 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-473." FT /evidence="ECO:0000269|PubMed:29211348" FT MUTAGEN 575 FT /note="S->E: Strongly reduced but still present interaction FT with 14-3-3 proteins in response to cAMP signaling and, FT thus, still able to inhibit TORC activity." FT /evidence="ECO:0000269|PubMed:29211348" FT CONFLICT 166 FT /note="A -> AGTE (in Ref. 3; BAA95536)" FT /evidence="ECO:0000305" FT CONFLICT 489..490 FT /note="IV -> KF (in Ref. 3; BAA95536)" FT /evidence="ECO:0000305" SQ SEQUENCE 783 AA; 84902 MW; D646123C0715DAAC CRC64; MVIMSEFSAD PAGQGQGQQK PLRVGFYDIE RTLGKGNFAV VKLARHRVTK TQVAIKIIDK TRLDSSNLEK IYREVQLMKL LNHPHIIKLY QVMETKDMLY IVTEFAKNGE MFDYLTSNGH LSENEARKKF WQILSAVEYC HDHHIVHRDL KTENLLLDGN MDIKLADFGF GNFYKSGEPL STWCGSPPYA APEVFEGKEY EGPQLDIWSL GVVLYVLVCG SLPFDGPNLP TLRQRVLEGR FRIPFFMSQD CESLIRRMLV VDPARRITIA QIRQHRWMRA EPCLPGPACP AFSAHSYTSN LGDYDEQALG IMQTLGVDRQ RTVESLQNSS YNHFAAIYYL LLERLKEYRN AQCARPGPAR QPRPRSSDLS GLEVPQEGLS TDPFRPALLC PQPQTLVQSV LQAEMDCELQ SSLQWPLFFP VDASCSGVFR PRPVSPSSLL DTAISEEARQ GPGLEEEQDT QESLPSSTGR RHTLAEVSTR LSPLTAPCIV VSPSTTASPA EGTSSDSCLT FSASKSPAGL SGTPATQGLL GACSPVRLAS PFLGSQSATP VLQAQGGLGG AVLLPVSFQE GRRASDTSLT QGLKAFRQQL RKTTRTKGFL GLNKIKGLAR QVCQAPASRA SRGGLSPFHA PAQSPGLHGG AAGSREGWSL LEEVLEQQRL LQLQHHPAAA PGCSQAPQPA PAPFVIAPCD GPGAAPLPST LLTSGLPLLP PPLLQTGASP VASAAQLLDT HLHIGTGPTA LPAVPPPRLA RLAPGCEPLG LLQGDCEMED LMPCSLGTFV LVQ //