SIK1_HUMAN
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 03-AUG-2022, entry version 202.
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; 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}.
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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; 42.
DR BioGRID; 3195539; 6.
DR IntAct; P57059; 28.
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 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; P57059; -.
DR PeptideAtlas; P57059; -.
DR PRIDE; P57059; -.
DR ProteomicsDB; 56978; -.
DR Antibodypedia; 9946; 318 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 CTD; 150094; -.
DR DisGeNET; 102724428; -.
DR DisGeNET; 150094; -.
DR GeneCards; SIK1; -.
DR HGNC; HGNC:11142; SIK1.
DR HPA; ENSG00000142178; Tissue enhanced (skin).
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; LHISAGP; -.
DR OrthoDB; 1127668at2759; -.
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 4 CRISPR screens.
DR BioGRID-ORCS; 150094; 14 hits in 1110 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 96 other tissues.
DR ExpressionAtlas; P57059; baseline and differential.
DR Genevisible; P57059; HS.
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:0042149; P:cellular response to glucose starvation; IBA:GO_Central.
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 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 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 14-
FT 3-3 proteins in response to cAMP signaling and, thus, still
FT able to inhibit TORC activity. Resistant to inhibition by
FT cAMP signaling and, thus, still able to inhibit TORC
FT 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 14-
FT 3-3 proteins in response to cAMP signaling and, thus, still
FT 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
