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Q60670 (SIK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 129. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Serine/threonine-protein kinase SIK1

EC=2.7.11.1
Alternative name(s):
HRT-20
Myocardial SNF1-like kinase
Salt-inducible kinase 1
Short name=SIK-1
Serine/threonine-protein kinase SNF1-like kinase 1
Short name=Serine/threonine-protein kinase SNF1LK
Gene names
Name:Sik1
Synonyms:Msk, Sik, Snf1lk
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length779 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, TORC1/CRTC1 and TORC2/CRTC2. Acts as a tumor suppressor and plays a key role in p53/TP53-dependent anoikis, a type of apoptosis triggered by cell detachment: required for phosphorylation of p53/TP53 in response to loss of adhesion and is able to suppress metastasis. Part of a sodium-sensing signaling network, probably by mediating phosphorylation of PPME1: following increases in intracellular sodium, SIK1 is activated by CaMK1 and phosphorylates PPME1 subunit of protein phosphatase 2A (PP2A), leading to dephosphorylation of sodium/potassium-transporting ATPase ATP1A1 and subsequent increase activity of ATP1A1. Acts as a regulator of muscle cells by phosphorylating and inhibiting class II histone deacetylases HDAC4 and HDAC5, leading to promote expression of MEF2 target genes in myocytes. Also required during cardiomyogenesis by regulating the exit of cardiomyoblasts from the cell cycle via down-regulation of CDKN1C/p57Kip2. Acts as a regulator of hepatic gluconeogenesis by phosphorylating and repressing the CREB-specific coactivators TORC1/CRTC1 and TORC2/CRTC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

Activated by phosphorylation on Thr-182. Also activated by phosphorylation on Thr-322 in response to increases in intracellular sodium in parallel with elevations in intracellular calcium through the reversible sodium/calcium exchanger. Ref.7

Subunit structure

Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ. Interacts with ATP1A1 By similarity.

Subcellular location

Cytoplasm. Nucleus. Note: Following ACTH (adrenocorticotropic hormone) treatment and subsequent phosphorylation by PKA, translocates to the cytoplasm, where it binds to YWHAZ. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7

Tissue specificity

Expressed in lung, skin, ovary, heart and stomach. No expression in brain, liver or adult skeletal muscle but is present in skeletal muscle progenitor cells of the somite beginning at 9.5 dpc. Present at 8.0 dpc in the monolayer of presumptive myocardial cells but rapidly down-regulated at 8.5 dpc upon primitive ventricle formation, although still present in myocardial cells that will populate the primitive atrium and bulbus cordis. At 9.5 dpc expression is down-regulated in the primitive atrium but observed in the sinus venosus and truncus arteriosus. Ref.1 Ref.5

Induction

Expression is stimulated by CREB1 in myocytes; direct target of CREB1. Ref.7 Ref.8

Domain

The RK-rich region determines the subcellular location. Ref.4

Post-translational modification

Phosphorylated at Thr-182 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39, leading to its activation. Phosphorylation at Thr-182 promotes autophosphorylation at Ser-186, which is required for sustained activity. Autophosphorylation at Ser-186 is maintained by sequential phosphorylation at Thr-182 by GSK3-beta. GSK3-beta cannot initiate phosphorylation at Thr-182, it can only maintain it. Phosphorylation at Ser-577 by PKA promotes translocation to the cytoplasm. Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation. Ref.3 Ref.7 Ref.8

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. AMPK subfamily.

Contains 1 protein kinase domain.

Contains 1 UBA domain.

Ontologies

Keywords
   Biological processCell cycle
Differentiation
   Cellular componentCytoplasm
Nucleus
   DiseaseTumor suppressor
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processanoikis

Inferred from mutant phenotype Ref.9. Source: BHF-UCL

cardiac muscle cell differentiation

Inferred from mutant phenotype Ref.11. Source: UniProtKB

cell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular signal transduction

Inferred from direct assay Ref.5. Source: UniProtKB

negative regulation of CREB transcription factor activity

Inferred from direct assay Ref.3Ref.6. Source: UniProtKB

negative regulation of gluconeogenesis

Inferred from direct assay Ref.6. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

negative regulation of triglyceride biosynthetic process

Inferred from direct assay Ref.10. Source: UniProtKB

positive regulation of anoikis

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.5. Source: UniProtKB

regulation of cell differentiation

Inferred from expression pattern Ref.5. Source: UniProtKB

regulation of mitotic cell cycle

Inferred from direct assay Ref.5. Source: UniProtKB

regulation of myotube differentiation

Inferred from direct assay Ref.8. Source: UniProtKB

regulation of sodium ion transport

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from direct assay Ref.3Ref.5Ref.7. Source: UniProtKB

cytosol

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from direct assay Ref.3Ref.7. Source: UniProtKB

   Molecular_function14-3-3 protein binding

Inferred from sequence or structural similarity. Source: UniProtKB

ATP binding

Inferred from direct assay Ref.5. Source: UniProtKB

cAMP response element binding protein binding

Inferred from direct assay Ref.3. Source: UniProtKB

histone deacetylase binding

Inferred from physical interaction Ref.8. Source: UniProtKB

magnesium ion binding

Inferred from direct assay Ref.5. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.10. Source: UniProtKB

protein kinase binding

Inferred from physical interaction Ref.3. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.5Ref.6Ref.8Ref.10. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 779779Serine/threonine-protein kinase SIK1
PRO_0000086660

Regions

Domain27 – 278252Protein kinase
Domain303 – 34341UBA
Nucleotide binding33 – 419ATP By similarity
Region586 – 61227RK-rich region

Sites

Active site1491Proton acceptor By similarity
Binding site561ATP

Amino acid modifications

Modified residue1821Phosphothreonine; by LKB1 and GSK3-beta Ref.7
Modified residue1861Phosphoserine; by autocatalysis By similarity
Modified residue3221Phosphothreonine; by CaMK1 By similarity
Modified residue5771Phosphoserine; by PKA Ref.3 Ref.7 Ref.8

Experimental info

Mutagenesis561K → M: Loss of kinase activity. Ref.5 Ref.7 Ref.8
Mutagenesis1821T → A: Loss of kinase activity. Ref.7
Mutagenesis1821T → E: Low levels of constitutive activity. Ref.7
Mutagenesis2681T → A: Does not affect phosphorylation by PKA and nuclear export following ACTH treatment. Ref.3
Mutagenesis4751T → A: Does not affect phosphorylation by PKA and nuclear export following ACTH treatment. Ref.3
Mutagenesis5771S → A: Abolishes phosphorylation by PKA and impairs nuclear export following ACTH treatment. Ref.3 Ref.7 Ref.8
Mutagenesis5771S → A: Constitutively active. Ref.3 Ref.7 Ref.8
Mutagenesis593 – 5942RK → AA: Localizes mainly in cytoplasm and not in nucleus.
Mutagenesis597 – 5993RTK → ATA: Localizes mainly in cytoplasm and not in nucleus. Ref.4
Mutagenesis606 – 6083KIK → AIA: Localizes mainly in cytoplasm and not in nucleus. Ref.4
Mutagenesis6071I → A: Localizes mainly in cytoplasm and not in nucleus; when associated with D-483 and A-610. Ref.4
Mutagenesis6101L → A: Localizes mainly in cytoplasm and not in nucleus; when associated with D-483 and A-607. Ref.4
Sequence conflict183 – 1842WC → CV in AAA67926. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q60670 [UniParc].

Last modified October 19, 2011. Version 3.
Checksum: 9C4D25CCF0C0D06D

FASTA77985,115
        10         20         30         40         50         60 
MVIMSEFSAV PSGTGQGQQK PLRVGFYDVE RTLGKGNFAV VKLARHRVTK TQVAIKIIDK 

        70         80         90        100        110        120 
TRLDSSNLEK IYREVQLMKL LNHPNIIKLY QVMETKDMLY IVTEFAKNGE MFDYLTSNGH 

       130        140        150        160        170        180 
LSENEARQKF WQILSAVEYC HNHHIVHRDL KTENLLLDSN MDIKLADFGF GNFYKPGEPL 

       190        200        210        220        230        240 
STWCGSPPYA APEVFEGKEY EGPQLDVWSL GVVLYVLVCG SLPFDGPNLP TLRQRVLEGR 

       250        260        270        280        290        300 
FRIPFFMSQD CETLIRRMLV VDPAKRITIA QIRQHRWMQA DPTLLQQDDP AFDMQGYTSN 

       310        320        330        340        350        360 
LGDYNEQVLG IMQALGIDRQ RTIESLQNSS YNHFAAIYYL LLERLKEHRS AQPSSRPTPA 

       370        380        390        400        410        420 
PTRQPQLRSS DLSSLEVPQE ILPCDPFRPS LLCPQPQALA QSVLQAEIDC DLHSSLQPLL 

       430        440        450        460        470        480 
FPLDTNCSGV FRHRSISPSS LLDTAISEEA RQGPSLEEEQ EVQEPLPGST GRRHTLAEVS 

       490        500        510        520        530        540 
THFSPLNPPC IIVSSSATAS PSEGTSSDSC LPFSASEGPA GLGSGLATPG LLGTSSPVRL 

       550        560        570        580        590        600 
ASPFLGSQSA TPVLQTQAGL GTAVLPPVSF QEGRRASDTS LTQGLKAFRQ QLRKNARTKG 

       610        620        630        640        650        660 
FLGLNKIKGL ARQVCQSSVR TPRGGMSTFH TPAPSSGLQG CTTSNREGRS LLEEVLHQQR 

       670        680        690        700        710        720 
LLQLQHHSST AAASSGCQQG PQLSPVPYVL APCDSLLVSG IPLLPTPLLQ AGMSPVASAA 

       730        740        750        760        770 
HLLDTHLHIS AGPVALPTGP LPQCLTRLSP GCDPAGLPQG DCEMEDLTSG QRGTFVLVQ 

« Hide

References

« Hide 'large scale' references
[1]"Identification of novel protein kinases expressed in the myocardium of the developing mouse heart."
Ruiz J.C., Conlon F.L., Robertson E.J.
Mech. Dev. 48:153-164(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
Tissue: Embryo.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J.
Tissue: Spinal ganglion.
[3]"ACTH-induced nucleocytoplasmic translocation of salt-inducible kinase. Implication in the protein kinase A-activated gene transcription in mouse adrenocortical tumor cells."
Takemori H., Katoh Y., Horike N., Doi J., Okamoto M.
J. Biol. Chem. 277:42334-42343(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-577, MUTAGENESIS OF THR-268; THR-475 AND SER-577.
[4]"Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm."
Katoh Y., Takemori H., Min L., Muraoka M., Doi J., Horike N., Okamoto M.
Eur. J. Biochem. 271:4307-4319(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, DOMAIN RK-RICH REGION, MUTAGENESIS OF 593-ARG-LYS-594; 597-ARG--LYS-599; 606-LYS--LYS-608; ILE-607 AND LEU-610.
[5]"snf1lk encodes a protein kinase that may function in cell cycle regulation."
Stephenson A., Huang G.Y., Nguyen N.T., Reuter S., McBride J.L., Ruiz J.C.
Genomics 83:1105-1115(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-56.
[6]"The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism."
Koo S.-H., Flechner L., Qi L., Zhang X., Screaton R.A., Jeffries S., Hedrick S., Xu W., Boussouar F., Brindle P., Takemori H., Montminy M.
Nature 437:1109-1111(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CRTC2, SUBCELLULAR LOCATION.
[7]"Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade."
Katoh Y., Takemori H., Lin X.-Z., Tamura M., Muraoka M., Satoh T., Tsuchiya Y., Min L., Doi J., Miyauchi A., Witters L.A., Nakamura H., Okamoto M.
FEBS J. 273:2730-2748(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-182 AND SER-577, MUTAGENESIS OF LYS-56; THR-182 AND SER-577.
[8]"SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes."
Berdeaux R., Goebel N., Banaszynski L., Takemori H., Wandless T., Shelton G.D., Montminy M.
Nat. Med. 13:597-603(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF HDAC4 AND HDAC5, INDUCTION, PHOSPHORYLATION AT SER-577, MUTAGENESIS OF LYS-56 AND SER-577.
[9]"SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis."
Cheng H., Liu P., Wang Z.C., Zou L., Santiago S., Garbitt V., Gjoerup O.V., Iglehart J.D., Miron A., Richardson A.L., Hahn W.C., Zhao J.J.
Sci. Signal. 2:RA35-RA35(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[10]"Salt-inducible kinase regulates hepatic lipogenesis by controlling SREBP-1c phosphorylation."
Yoon Y.S., Seo W.Y., Lee M.W., Kim S.T., Koo S.H.
J. Biol. Chem. 284:10446-10452(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF SREBF1.
[11]"Lack of sik1 in mouse embryonic stem cells impairs cardiomyogenesis by down-regulating the cyclin-dependent kinase inhibitor p57kip2."
Romito A., Lonardo E., Roma G., Minchiotti G., Ballabio A., Cobellis G.
PLoS ONE 5:E9029-E9029(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U11494 mRNA. Translation: AAA67926.2.
AK141817 mRNA. Translation: BAE24842.1.
CCDSCCDS37552.1.
PIRI49072.
RefSeqNP_034961.2. NM_010831.2.
UniGeneMm.290941.

3D structure databases

ProteinModelPortalQ60670.
SMRQ60670. Positions 24-341.
ModBaseSearch...
MobiDBSearch...

PTM databases

PhosphoSiteQ60670.

Proteomic databases

PRIDEQ60670.

Protocols and materials databases

DNASU17691.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000024839; ENSMUSP00000024839; ENSMUSG00000024042.
GeneID17691.
KEGGmmu:17691.
UCSCuc008bvr.1. mouse.

Organism-specific databases

CTD150094.
MGIMGI:104754. Sik1.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117510.
HOGENOMHOG000039981.
InParanoidQ60670.
KOK16311.
OMAQIRQHRW.
OrthoDBEOG70ZZMM.
TreeFamTF315213.

Gene expression databases

ArrayExpressQ60670.
BgeeQ60670.
CleanExMM_SNF1LK.
GenevestigatorQ60670.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR017090. Ser/Thr_kinase_SIK1/2.
IPR015940. UBA/transl_elong_EF1B_N_euk.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF037014. Ser/Thr_PK_SNF1-like. 1 hit.
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50030. UBA. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio292274.
PROQ60670.
SOURCESearch...

Entry information

Entry nameSIK1_MOUSE
AccessionPrimary (citable) accession number: Q60670
Secondary accession number(s): Q3UR46
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: October 19, 2011
Last modified: July 9, 2014
This is version 129 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot