SIK1_RAT
ID SIK1_RAT Reviewed; 776 AA.
AC Q9R1U5; Q9R081;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=Serine/threonine-protein kinase SIK1;
DE EC=2.7.11.1 {ECO:0000269|PubMed:17939993};
DE AltName: Full=Protein kinase KID2;
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=Kid2, Sik, Snf1lk;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AUTOPHOSPHORYLATION, AND INDUCTION.
RC STRAIN=Sprague-Dawley; TISSUE=Adrenal gland;
RX PubMed=10403390; DOI=10.1016/s0014-5793(99)00708-5;
RA Wang Z., Takemori H., Halder S.K., Nonaka Y., Okamoto M.;
RT "Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt
RT diet-treated rat adrenal.";
RL FEBS Lett. 453:135-139(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INDUCTION.
RX PubMed=10820182; DOI=10.1046/j.1471-4159.2000.0742227.x;
RA Feldman J.D., Vician L., Crispino M., Hoe W., Baudry M., Herschman H.R.;
RT "The salt-inducible kinase, SIK, is induced by depolarization in brain.";
RL J. Neurochem. 74:2227-2238(2000).
RN [3]
RP FUNCTION IN PHOSPHORYLATION OF PPME1, CATALYTIC ACTIVITY, PHOSPHORYLATION
RP AT THR-322, MUTAGENESIS OF THR-322, AND INTERACTION WITH ATP1A1.
RX PubMed=17939993; DOI=10.1073/pnas.0706838104;
RA Sjostrom M., Stenstrom K., Eneling K., Zwiller J., Katz A.I., Takemori H.,
RA Bertorello A.M.;
RT "SIK1 is part of a cell sodium-sensing network that regulates active sodium
RT transport through a calcium-dependent process.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:16922-16927(2007).
RN [4]
RP FUNCTION.
RX PubMed=18946175; DOI=10.1507/endocrj.k08e-173;
RA Takemori H., Katoh Hashimoto Y., Nakae J., Olson E.N., Okamoto M.;
RT "Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts.";
RL Endocr. J. 56:121-130(2009).
RN [5]
RP FUNCTION IN PHOSPHORYLATION OF CRTC1, AND SUBCELLULAR LOCATION.
RX PubMed=19244510; DOI=10.1523/jneurosci.2296-08.2009;
RA Li S., Zhang C., Takemori H., Zhou Y., Xiong Z.Q.;
RT "TORC1 regulates activity-dependent CREB-target gene transcription and
RT dendritic growth of developing cortical neurons.";
RL J. Neurosci. 29:2334-2343(2009).
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 and
CC CRTC2/TORC2. Acts as a tumor suppressor and plays a key role in
CC p53/TP53-dependent anoikis, a type of apoptosis triggered by cell
CC detachment: required for phosphorylation of p53/TP53 in response to
CC loss of adhesion and is able to suppress metastasis. Part of a sodium-
CC sensing signaling network, probably by mediating phosphorylation of
CC PPME1: following increases in intracellular sodium, SIK1 is activated
CC by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A
CC (PP2A), leading to dephosphorylation of sodium/potassium-transporting
CC ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a
CC regulator of muscle cells by phosphorylating and inhibiting class II
CC histone deacetylases HDAC4 and HDAC5, leading to promote expression of
CC MEF2 target genes in myocytes. Also required during cardiomyogenesis by
CC regulating the exit of cardiomyoblasts from the cell cycle via down-
CC regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic
CC gluconeogenesis by phosphorylating and repressing the CREB-specific
CC coactivators CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB
CC activity. Also regulates hepatic lipogenesis by phosphorylating and
CC inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-
CC induced entrainment of the circadian clock by attenuating PER1
CC induction; represses CREB-mediated transcription of PER1 by
CC phosphorylating and deactivating CRTC1/TORC1 (By similarity).
CC {ECO:0000250|UniProtKB:Q60670, ECO:0000269|PubMed:10820182,
CC ECO:0000269|PubMed:17939993, ECO:0000269|PubMed:18946175,
CC ECO:0000269|PubMed:19244510}.
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:17939993};
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:17939993};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-182 (By
CC similarity). Also activated by phosphorylation on Thr-322 in response
CC to increases in intracellular sodium in parallel with elevations in
CC intracellular calcium through the reversible sodium/calcium exchanger.
CC {ECO:0000250}.
CC -!- SUBUNIT: Interacts (when phosphorylated on Thr-182 and Ser-186) with
CC YWHAZ (By similarity). Interacts with ATP1A1. {ECO:0000250,
CC ECO:0000269|PubMed:17939993}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19244510}. Nucleus
CC {ECO:0000269|PubMed:19244510}. Note=Following ACTH (adrenocorticotropic
CC hormone) treatment and subsequent phosphorylation by PKA, translocates
CC to the cytoplasm, where it binds to YWHAZ.
CC -!- INDUCTION: By high salt diet and depolarization in brain.
CC {ECO:0000269|PubMed:10403390, ECO:0000269|PubMed:10820182}.
CC -!- DOMAIN: The RK-rich region determines the subcellular location.
CC {ECO:0000250}.
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-577 by PKA promotes
CC translocation to the cytoplasm (By similarity). Phosphorylation at Thr-
CC 322 by CaMK1 following intracellular sodium concentration leads to
CC activation. {ECO:0000250, ECO:0000269|PubMed:17939993}.
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; AB020480; BAA82673.1; -; mRNA.
DR EMBL; AF106937; AAF14191.1; -; mRNA.
DR RefSeq; NP_067725.2; NM_021693.2.
DR AlphaFoldDB; Q9R1U5; -.
DR SMR; Q9R1U5; -.
DR DIP; DIP-46210N; -.
DR IntAct; Q9R1U5; 1.
DR STRING; 10116.ENSRNOP00000001579; -.
DR iPTMnet; Q9R1U5; -.
DR PhosphoSitePlus; Q9R1U5; -.
DR PaxDb; Q9R1U5; -.
DR Ensembl; ENSRNOT00000001579; ENSRNOP00000001579; ENSRNOG00000001189.
DR GeneID; 59329; -.
DR KEGG; rno:59329; -.
DR UCSC; RGD:69407; rat.
DR CTD; 150094; -.
DR RGD; 69407; Sik1.
DR eggNOG; KOG0586; Eukaryota.
DR GeneTree; ENSGT00940000154989; -.
DR HOGENOM; CLU_000288_87_2_1; -.
DR InParanoid; Q9R1U5; -.
DR OMA; LHISAGP; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q9R1U5; -.
DR TreeFam; TF315213; -.
DR PRO; PR:Q9R1U5; -.
DR Proteomes; UP000002494; Chromosome 20.
DR Bgee; ENSRNOG00000001189; Expressed in lung and 18 other tissues.
DR Genevisible; Q9R1U5; RN.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0071889; F:14-3-3 protein binding; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0008140; F:cAMP response element binding protein binding; ISS:UniProtKB.
DR GO; GO:0042826; F:histone deacetylase binding; ISO:RGD.
DR GO; GO:0000287; F:magnesium ion binding; ISS: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; ISO:RGD.
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; ISS: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:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:RGD.
DR GO; GO:0010868; P:negative regulation of triglyceride biosynthetic process; ISS:UniProtKB.
DR GO; GO:2000210; P:positive regulation of anoikis; ISO:RGD.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IMP:RGD.
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; IDA: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; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Tumor suppressor.
FT CHAIN 1..776
FT /note="Serine/threonine-protein kinase SIK1"
FT /id="PRO_0000086661"
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 350..371
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 449..472
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 586..612
FT /note="RK-rich region"
FT /evidence="ECO:0000250"
FT REGION 621..643
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 352..371
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:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 182
FT /note="Phosphothreonine; by LKB1 and GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:P57059"
FT MOD_RES 186
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P57059"
FT MOD_RES 322
FT /note="Phosphothreonine; by CaMK1"
FT /evidence="ECO:0000269|PubMed:17939993"
FT MOD_RES 577
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:Q60670"
FT MUTAGEN 322
FT /note="T->A: Abolishes ability to regulate
FT sodium/potassium-transporting ATPase activity following
FT increases in intracellular sodium."
FT /evidence="ECO:0000269|PubMed:17939993"
FT CONFLICT 473
FT /note="R -> K (in Ref. 2; AAF14191)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 776 AA; 84909 MW; 7BF745AF28F17E6E CRC64;
MVIMSEFSAV PTGTGQGQQK PLRVGFYDVE RTLGKGNFAV VKLARHRVTK TQVAIKIIDK
TRLDSSNLEK IYREVQLMKL LNHPNIIKLY QVMETKDMLY IVTEFAKNGE MFDYLTSNGH
LSENEARKKF WQILSAVEYC HNHHIVHRDL KTENLLLDGN MDIKLADFGF GNFYKPGEPL
STWCGSPPYA APEVFEGKEY EGPQLDIWSL GVVLYVLVCG SLPFDGPNLP TLRQRVLEGR
FRIPFFMSQD CETLIRRMLV VDPAKRITIA QIRQHRWMQA DPTLLQQDDP AFSMQGYTSN
LGDYNEQVLG IMQALGIDRQ RTVESLQNSS YNHFAAIYYL LLERLREHRS TQPSSRATPA
PARQPQLRNS DLSSLEVPQE ILPCDPFRPS LLCPQPQALA QSVLQAEIDC DLHSSLQPLF
FPLDTNCSGV FRHRSISPSS LLDTAISEEA RQGPSLEEEQ EVQEPLPGST GRRHTLAEVS
THFSPLNPPC IIVSSSAAVS PSEGTSSDSC LPFSASEGPA GLGGGLATPG LLGTSSPVRL
ASPFLGSQSA TPVLQSQAGL GATVLPPVSF QEGRRASDTS LTQGLKAFRQ QLRKNARTKG
FLGLNKIKGL ARQVCQSSIR GSRGGMSTFH TPAPSSGLQG CTASSREGRS LLEEVLHQQR
LLQLQHHSAV SSDYQQAPQL SPVPYVLTPC DGLLVSGIPL LPTPLLQPGM SPVASAAQLL
DAHLHISAGP VALPTGPLPQ CLTRLSPSCD PAGLPQGDCE MEDLTSGQRG TFVLVQ
