SIK3_HUMAN
ID SIK3_HUMAN Reviewed; 1321 AA.
AC Q9Y2K2; A1A5A8; H0Y494; J3KPC8; Q59FY2; Q5M9N1; Q6P3R6; Q8IYM8; Q9HA50;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 28-MAR-2018, sequence version 4.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Serine/threonine-protein kinase SIK3 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000269|PubMed:29211348};
DE AltName: Full=Salt-inducible kinase 3;
DE Short=SIK-3;
DE AltName: Full=Serine/threonine-protein kinase QSK;
GN Name=SIK3 {ECO:0000312|HGNC:HGNC:29165};
GN Synonyms=KIAA0999 {ECO:0000303|PubMed:10231032},
GN QSK {ECO:0000303|PubMed:14976552}; ORFNames=L19;
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, ACTIVITY REGULATION, PHOSPHORYLATION
RP AT THR-221, AND MUTAGENESIS OF THR-221.
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE
RP [MRNA] OF 47-1321 (ISOFORM 4), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF
RP 725-1321 (ISOFORM 3), AND NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF
RP 816-1321 (ISOFORM 1).
RC TISSUE=Testis, and Uterus;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 8-1321 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10231032; DOI=10.1093/dnares/6.1.63;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:63-70(1999).
RN [5]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 331-1321 (ISOFORM 1), AND VARIANT
RP ARG-1136.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 816-1321 (ISOFORM 1).
RC TISSUE=Mammary gland;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 817-1321 (ISOFORM 1).
RX PubMed=15334068; DOI=10.1038/sj.onc.1207921;
RA Petroziello J., Yamane A., Westendorf L., Thompson M., McDonagh C.,
RA Cerveny C., Law C.-L., Wahl A., Carter P.;
RT "Suppression subtractive hybridization and expression profiling identifies
RT a unique set of genes overexpressed in non-small-cell lung cancer.";
RL Oncogene 23:7734-7745(2004).
RN [9]
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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-626, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-71; THR-221; SER-551; SER-626
RP AND SER-866, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-113 (ISOFORM 2), AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-221; THR-469; SER-551;
RP SER-626 AND SER-866, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-469; SER-626 AND SER-978, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [15]
RP FUNCTION, INTERACTION WITH 14-3-3 PROTEINS, PTM, AND MUTAGENESIS OF
RP THR-469; SER-551 AND SER-626.
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 [16]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-389 AND VAL-1161.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [17]
RP INVOLVEMENT IN SEMDK, VARIANT SEMDK CYS-187, CHARACTERIZATION OF VARIANT
RP SEMDK CYS-187, FUNCTION, INTERACTION WITH DEPTOR; MLST8; RICTOR AND RPTOR,
RP CATALYTIC ACTIVITY, TISSUE SPECIFICITY, AND PHOSPHORYLATION AT THR-221.
RX PubMed=30232230; DOI=10.1126/scitranslmed.aat9356;
RA Csukasi F., Duran I., Barad M., Barta T., Gudernova I., Trantirek L.,
RA Martin J.H., Kuo C.Y., Woods J., Lee H., Cohn D.H., Krejci P., Krakow D.;
RT "The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR
RT signaling.";
RL Sci. Transl. Med. 10:0-0(2018).
CC -!- FUNCTION: Positive regulator of mTOR signaling that functions by
CC triggering the degradation of DEPTOR, an mTOR inhibitor. Involved in
CC the dynamic regulation of mTOR signaling in chondrocyte differentiation
CC during skeletogenesis (PubMed:30232230). Negatively regulates cAMP
CC signaling pathway possibly by acting on CRTC2/TORC2 and CRTC3/TORC3
CC (Probable). Prevents HDAC4 translocation to the nucleus (By
CC similarity). {ECO:0000250|UniProtKB:Q6P4S6,
CC ECO:0000269|PubMed:30232230, ECO:0000305|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:30232230};
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:30232230};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9H0K1};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-221.
CC {ECO:0000250|UniProtKB:Q9H0K1}.
CC -!- SUBUNIT: Binds to and is activated by YWHAZ when phosphorylated on Thr-
CC 221 (PubMed:16306228). Interacts with 14-3-3 proteins
CC (PubMed:29211348). Interacts with HDAC4; this interaction leads to
CC HDAC4 retention in the cytoplasm (By similarity). Interacts with
CC DEPTOR, MLST8/GbetaL, RICTOR and RPTOR (PubMed:30232230).
CC {ECO:0000250|UniProtKB:Q6P4S6, ECO:0000269|PubMed:16306228,
CC ECO:0000269|PubMed:29211348, ECO:0000269|PubMed:30232230}.
CC -!- INTERACTION:
CC Q9Y2K2; P63104: YWHAZ; NbExp=5; IntAct=EBI-1181460, EBI-347088;
CC Q9Y2K2-7; P42858: HTT; NbExp=3; IntAct=EBI-17172855, EBI-466029;
CC Q9Y2K2-7; Q13077: TRAF1; NbExp=3; IntAct=EBI-17172855, EBI-359224;
CC Q9Y2K2-7; Q15654: TRIP6; NbExp=3; IntAct=EBI-17172855, EBI-742327;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16306228}.
CC Note=Locates to punctate structures within the cytoplasm on binding to
CC YWHAZ. {ECO:0000269|PubMed:16306228}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q9Y2K2-5; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y2K2-6; Sequence=VSP_059412, VSP_059415;
CC Name=3;
CC IsoId=Q9Y2K2-7; Sequence=VSP_059416, VSP_059417;
CC Name=4;
CC IsoId=Q9Y2K2-8; Sequence=VSP_059413, VSP_059414, VSP_059415;
CC -!- TISSUE SPECIFICITY: Expressed in chondrocytes.
CC {ECO:0000269|PubMed:30232230}.
CC -!- PTM: Phosphorylated at Thr-221 by STK11/LKB1 in complex with STE20-
CC related adapter-alpha (STRADA) pseudo kinase and CAB39
CC (PubMed:14976552). Phosphorylation at Thr-221 is inhibited in response
CC to PTHLH/PTHrP (PubMed:30232230). Phosphorylated at Thr-469 and Ser-551
CC in response to cAMP signaling (Probable). {ECO:0000269|PubMed:14976552,
CC ECO:0000269|PubMed:30232230, ECO:0000305|PubMed:29211348}.
CC -!- DISEASE: Spondyloepimetaphyseal dysplasia, Krakow type (SEMDK)
CC [MIM:618162]: An autosomal recessive skeletal disorder characterized by
CC severe spondyloepimetaphyseal dysplasia, rhizomelia, mesomelia with
CC significant anterior bowing of all limbs, severe immunodeficiency, and
CC developmental delay. {ECO:0000269|PubMed:30232230}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. SNF1 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH63887.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAI28511.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA76843.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAB14006.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB023216; BAA76843.2; ALT_INIT; mRNA.
DR EMBL; AP000936; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP003070; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP006216; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC035583; AAH35583.3; -; mRNA.
DR EMBL; BC063887; AAH63887.1; ALT_INIT; mRNA.
DR EMBL; BC086858; AAH86858.1; -; mRNA.
DR EMBL; BC128510; AAI28511.1; ALT_INIT; mRNA.
DR EMBL; AB209327; BAD92564.1; -; mRNA.
DR EMBL; AK022302; BAB14006.1; ALT_INIT; mRNA.
DR EMBL; AY598338; AAT06749.1; -; mRNA.
DR CCDS; CCDS60974.1; -. [Q9Y2K2-8]
DR CCDS; CCDS8379.2; -. [Q9Y2K2-5]
DR RefSeq; NP_001268678.1; NM_001281749.1. [Q9Y2K2-8]
DR RefSeq; NP_079440.3; NM_025164.4. [Q9Y2K2-5]
DR AlphaFoldDB; Q9Y2K2; -.
DR SMR; Q9Y2K2; -.
DR BioGRID; 116963; 34.
DR IntAct; Q9Y2K2; 45.
DR MINT; Q9Y2K2; -.
DR STRING; 9606.ENSP00000364449; -.
DR BindingDB; Q9Y2K2; -.
DR ChEMBL; CHEMBL6149; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9Y2K2; -.
DR GuidetoPHARMACOLOGY; 2199; -.
DR iPTMnet; Q9Y2K2; -.
DR PhosphoSitePlus; Q9Y2K2; -.
DR BioMuta; SIK3; -.
DR DMDM; 115502238; -.
DR EPD; Q9Y2K2; -.
DR jPOST; Q9Y2K2; -.
DR MassIVE; Q9Y2K2; -.
DR MaxQB; Q9Y2K2; -.
DR PaxDb; Q9Y2K2; -.
DR PeptideAtlas; Q9Y2K2; -.
DR PRIDE; Q9Y2K2; -.
DR ProteomicsDB; 108; -.
DR ProteomicsDB; 34706; -.
DR ABCD; Q9Y2K2; 6 sequenced antibodies.
DR Antibodypedia; 56803; 167 antibodies from 27 providers.
DR DNASU; 23387; -.
DR Ensembl; ENST00000375300.6; ENSP00000364449.1; ENSG00000160584.17. [Q9Y2K2-5]
DR Ensembl; ENST00000446921.6; ENSP00000390442.2; ENSG00000160584.17. [Q9Y2K2-8]
DR GeneID; 23387; -.
DR KEGG; hsa:23387; -.
DR CTD; 23387; -.
DR DisGeNET; 23387; -.
DR GeneCards; SIK3; -.
DR HGNC; HGNC:29165; SIK3.
DR HPA; ENSG00000160584; Low tissue specificity.
DR MalaCards; SIK3; -.
DR MIM; 614776; gene.
DR MIM; 618162; phenotype.
DR neXtProt; NX_Q9Y2K2; -.
DR OpenTargets; ENSG00000160584; -.
DR PharmGKB; PA165543631; -.
DR VEuPathDB; HostDB:ENSG00000160584; -.
DR eggNOG; KOG0586; Eukaryota.
DR GeneTree; ENSGT00940000157259; -.
DR InParanoid; Q9Y2K2; -.
DR OMA; CQQLKED; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q9Y2K2; -.
DR TreeFam; TF315213; -.
DR PathwayCommons; Q9Y2K2; -.
DR SignaLink; Q9Y2K2; -.
DR SIGNOR; Q9Y2K2; -.
DR BioGRID-ORCS; 23387; 23 hits in 1008 CRISPR screens.
DR ChiTaRS; SIK3; human.
DR GeneWiki; KIAA0999; -.
DR GenomeRNAi; 23387; -.
DR Pharos; Q9Y2K2; Tchem.
DR PRO; PR:Q9Y2K2; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q9Y2K2; protein.
DR Bgee; ENSG00000160584; Expressed in lateral globus pallidus and 206 other tissues.
DR ExpressionAtlas; Q9Y2K2; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
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:0050321; F:tau-protein kinase activity; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0000226; P:microtubule cytoskeleton organization; IBA:GO_Central.
DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IMP:UniProtKB.
DR GO; GO:1904515; P:positive regulation of TORC2 signaling; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; 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; IPR034672; SIK.
DR InterPro; IPR015940; UBA.
DR Pfam; PF00069; Pkinase; 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 Alternative splicing; ATP-binding; Cytoplasm; Disease variant; Dwarfism;
KW Kinase; Magnesium; Metal-binding; Methylation; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1..1321
FT /note="Serine/threonine-protein kinase SIK3"
FT /id="PRO_0000252257"
FT DOMAIN 66..317
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 344..384
FT /note="UBA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT REGION 1..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 585..614
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 727..772
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 894..945
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1256..1289
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 597..614
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 740..772
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 897..916
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 188
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 72..80
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 95
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 71
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 221
FT /note="Phosphothreonine; by LKB1"
FT /evidence="ECO:0000269|PubMed:14976552,
FT ECO:0000269|PubMed:30232230, ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 469
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:29211348,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT MOD_RES 551
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 591
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6P4S6"
FT MOD_RES 592
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6P4S6"
FT MOD_RES 626
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 647
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6P4S6"
FT MOD_RES 866
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 978
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 986
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q6P4S6"
FT VAR_SEQ 1..760
FT /note="MAAAAASGAGGAAGAGTGGAGPAGRLLPPPAPGSPAAPAAVSPAAGQPRPPA
FT PASRGPMPARIGYYEIDRTIGKGNFAVVKRATHLVTKAKVAIKIIDKTQLDEENLKKIF
FT REVQIMKMLCHPHIIRLYQVMETERMIYLVTEYASGGEIFDHLVAHGRMAEKEARRKFK
FT QIVTAVYFCHCRNIVHRDLKAENLLLDANLNIKIADFGFSNLFTPGQLLKTWCGSPPYA
FT APELFEGKEYDGPKVDIWSLGVVLYVLVCGALPFDGSTLQNLRARVLSGKFRIPFFMST
FT ECEHLIRHMLVLDPNKRLSMEQICKHKWMKLGDADPNFDRLIAECQQLKEERQVDPLNE
FT DVLLAMEDMGLDKEQTLQSLRSDAYDHYSAIYSLLCDRHKRHKTLRLGALPSMPRALAF
FT QAPVNIQAEQAGTAMNISVPQVQLINPENQIVEPDGTLNLDSDEGEEPSPEALVRYLSM
FT RRHTVGVADPRTEVMEDLQKLLPGFPGVNPQAPFLQVAPNVNFMHNLLPMQNLQPTGQL
FT EYKEQSLLQPPTLQLLNGMGPLGRRASDGGANIQLHAQQLLKRPRGPSPLVTMTPAVPA
FT VTPVDEESSDGEPDQEAVQSSTYKDSNTLHLPTERFSPVRRFSDGAASIQAFKAHLEKM
FT GNNSSIKQLQQECEQLQKMYGGQIDERTLEKTQQQHMLYQQEQHHQILQQQIQDSICPP
FT QPSPPLQAACENQPALLTHQLQRLRIQPSSPPPNHPNNHLFRQPSNSPPPMSSAMIQPH
FT -> MACSTPHGSNRRLPRKCHFSLPTRTPTLCTSLRSVSPLCAGSQMGLRASRPSKLTW
FT KKWATTAASNSCSRSVSSCRRCTGGRLMKEPWRRPSSSICYTSRSSTIKFSSNKFKTLS
FT VLLSHLHLFRLHVKISQPSLPISSR (in isoform 2)"
FT /id="VSP_059412"
FT VAR_SEQ 365..412
FT /note="Missing (in isoform 4)"
FT /id="VSP_059413"
FT VAR_SEQ 603
FT /note="S -> RYLANRSKRHTLAMTNPTAEIPPDLQRQLGQQPFRSRVWPPHLVPDQ
FT HR (in isoform 4)"
FT /id="VSP_059414"
FT VAR_SEQ 874..933
FT /note="Missing (in isoform 2 and isoform 4)"
FT /id="VSP_059415"
FT VAR_SEQ 1171..1187
FT /note="EPVIGNCMDRSSPGQAV -> GKCLLTVEVLGQSALIN (in isoform
FT 3)"
FT /id="VSP_059416"
FT VAR_SEQ 1188..1321
FT /note="Missing (in isoform 3)"
FT /id="VSP_059417"
FT VARIANT 187
FT /note="R -> C (in SEMDK; decreased protein expression;
FT decreased kinase activity; no effect on the interaction
FT with DEPTOR, MLST8/GbetaL, RICTOR and RPTOR;
FT dbSNP:rs1565460853)"
FT /evidence="ECO:0000269|PubMed:30232230"
FT /id="VAR_081542"
FT VARIANT 389
FT /note="H -> L (in a breast cancer sample; somatic mutation;
FT dbSNP:rs376144593)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035634"
FT VARIANT 1098
FT /note="D -> E (in dbSNP:rs11216163)"
FT /id="VAR_051662"
FT VARIANT 1136
FT /note="P -> R (in dbSNP:rs12225230)"
FT /evidence="ECO:0000269|Ref.6"
FT /id="VAR_051663"
FT VARIANT 1161
FT /note="A -> V (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035635"
FT MUTAGEN 221
FT /note="T->A: Prevents phosphorylation and activation by
FT STK11/LKB1 complex."
FT /evidence="ECO:0000269|PubMed:14976552"
FT MUTAGEN 469
FT /note="T->A: Loss of interaction with 14-3-3 proteins in
FT response to cAMP signaling; inhibits cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 469
FT /note="T->E: Loss of interaction with 14-3-3 proteins in
FT response to cAMP signaling; inhibits cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 551
FT /note="S->A: Loss of interaction with 14-3-3 proteins in
FT response to cAMP signaling; inhibits cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 551
FT /note="S->E: Loss of interaction with 14-3-3 proteins in
FT response to cAMP signaling; inhibits cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 626
FT /note="S->A: No effect on interaction with 14-3-3 proteins,
FT nor on cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MUTAGEN 626
FT /note="S->E: No effect on cAMP signaling."
FT /evidence="ECO:0000269|PubMed:29211348"
FT MOD_RES Q9Y2K2-6:113
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19690332"
SQ SEQUENCE 1321 AA; 144851 MW; 84FA57F6BB5505DA CRC64;
MAAAAASGAG GAAGAGTGGA GPAGRLLPPP APGSPAAPAA VSPAAGQPRP PAPASRGPMP
ARIGYYEIDR TIGKGNFAVV KRATHLVTKA KVAIKIIDKT QLDEENLKKI FREVQIMKML
CHPHIIRLYQ VMETERMIYL VTEYASGGEI FDHLVAHGRM AEKEARRKFK QIVTAVYFCH
CRNIVHRDLK AENLLLDANL NIKIADFGFS NLFTPGQLLK TWCGSPPYAA PELFEGKEYD
GPKVDIWSLG VVLYVLVCGA LPFDGSTLQN LRARVLSGKF RIPFFMSTEC EHLIRHMLVL
DPNKRLSMEQ ICKHKWMKLG DADPNFDRLI AECQQLKEER QVDPLNEDVL LAMEDMGLDK
EQTLQSLRSD AYDHYSAIYS LLCDRHKRHK TLRLGALPSM PRALAFQAPV NIQAEQAGTA
MNISVPQVQL INPENQIVEP DGTLNLDSDE GEEPSPEALV RYLSMRRHTV GVADPRTEVM
EDLQKLLPGF PGVNPQAPFL QVAPNVNFMH NLLPMQNLQP TGQLEYKEQS LLQPPTLQLL
NGMGPLGRRA SDGGANIQLH AQQLLKRPRG PSPLVTMTPA VPAVTPVDEE SSDGEPDQEA
VQSSTYKDSN TLHLPTERFS PVRRFSDGAA SIQAFKAHLE KMGNNSSIKQ LQQECEQLQK
MYGGQIDERT LEKTQQQHML YQQEQHHQIL QQQIQDSICP PQPSPPLQAA CENQPALLTH
QLQRLRIQPS SPPPNHPNNH LFRQPSNSPP PMSSAMIQPH GAASSSQFQG LPSRSAIFQQ
QPENCSSPPN VALTCLGMQQ PAQSQQVTIQ VQEPVDMLSN MPGTAAGSSG RGISISPSAG
QMQMQHRTNL MATLSYGHRP LSKQLSADSA EAHSLNVNRF SPANYDQAHL HPHLFSDQSR
GSPSSYSPST GVGFSPTQAL KVPPLDQFPT FPPSAHQQPP HYTTSALQQA LLSPTPPDYT
RHQQVPHILQ GLLSPRHSLT GHSDIRLPPT EFAQLIKRQQ QQRQQQQQQQ QQQEYQELFR
HMNQGDAGSL APSLGGQSMT ERQALSYQNA DSYHHHTSPQ HLLQIRAQEC VSQASSPTPP
HGYAHQPALM HSESMEEDCS CEGAKDGFQD SKSSSTLTKG CHDSPLLLST GGPGDPESLL
GTVSHAQELG IHPYGHQPTA AFSKNKVPSR EPVIGNCMDR SSPGQAVELP DHNGLGYPAR
PSVHEHHRPR ALQRHHTIQN SDDAYVQLDN LPGMSLVAGK ALSSARMSDA VLSQSSLMGS
QQFQDGENEE CGASLGGHEH PDLSDGSQHL NSSCYPSTCI TDILLSYKHP EVSFSMEQAG
V
