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Protein

Serine/threonine-protein kinase SIK1

Gene

Sik1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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, CRTC1/TORC1 and CRTC2/TORC2. 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 CRTC1/TORC1 and CRTC2/TORC2, leading to inhibit CREB activity. Also regulates hepatic lipogenesis by phosphorylating and inhibiting SREBF1. In concert with CRTC1/TORC1, regulates the light-induced entrainment of the circadian clock by attenuating PER1 induction; represses CREB-mediated transcription of PER1 by phosphorylating and deactivating CRTC1/TORC1 (By similarity).By similarity4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Enzyme regulationi

Activated by phosphorylation on Thr-182 (By similarity). 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.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei56 – 561ATPPROSITE-ProRule annotation
Active sitei149 – 1491Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi33 – 419ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • 14-3-3 protein binding Source: UniProtKB
  • ATP binding Source: UniProtKB
  • cAMP response element binding protein binding Source: UniProtKB
  • magnesium ion binding Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Biological rhythms, Cell cycle, Differentiation

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase SIK1 (EC:2.7.11.1)
Alternative name(s):
Protein kinase KID2
Salt-inducible kinase 1
Short name:
SIK-1
Serine/threonine-protein kinase SNF1-like kinase 1
Short name:
Serine/threonine-protein kinase SNF1LK
Gene namesi
Name:Sik1
Synonyms:Kid2, Sik, Snf1lk
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 20

Organism-specific databases

RGDi69407. Sik1.

Subcellular locationi

  • Cytoplasm 1 Publication
  • Nucleus 1 Publication

  • Note: Following ACTH (adrenocorticotropic hormone) treatment and subsequent phosphorylation by PKA, translocates to the cytoplasm, where it binds to YWHAZ.

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: RGD
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi322 – 3221T → A: Abolishes ability to regulate sodium/potassium-transporting ATPase activity following increases in intracellular sodium. 1 Publication

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 776776Serine/threonine-protein kinase SIK1PRO_0000086661Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei182 – 1821Phosphothreonine; by LKB1 and GSK3-betaBy similarity
Modified residuei186 – 1861Phosphoserine; by autocatalysisBy similarity
Modified residuei322 – 3221Phosphothreonine; by CaMK11 Publication
Modified residuei577 – 5771Phosphoserine; by PKABy similarity

Post-translational modificationi

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 (By similarity). Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation.By similarity1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ9R1U5.
PRIDEiQ9R1U5.

PTM databases

iPTMnetiQ9R1U5.
PhosphoSiteiQ9R1U5.

Expressioni

Inductioni

By high salt diet and depolarization in brain.2 Publications

Gene expression databases

GenevisibleiQ9R1U5. RN.

Interactioni

Subunit structurei

Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ (By similarity). Interacts with ATP1A1.By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-46210N.
STRINGi10116.ENSRNOP00000001579.

Structurei

3D structure databases

ProteinModelPortaliQ9R1U5.
SMRiQ9R1U5. Positions 24-341.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini27 – 278252Protein kinasePROSITE-ProRule annotationAdd
BLAST
Domaini303 – 34341UBAPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni586 – 61227RK-rich regionBy similarityAdd
BLAST

Domaini

The RK-rich region determines the subcellular location.By similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 UBA domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0586. Eukaryota.
ENOG410XNQ0. LUCA.
GeneTreeiENSGT00790000122947.
HOGENOMiHOG000039981.
InParanoidiQ9R1U5.
KOiK19008.
OMAiPPCIVVS.
OrthoDBiEOG70ZZMM.
PhylomeDBiQ9R1U5.
TreeFamiTF315213.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
IPR017090. Ser/Thr_kinase_SIK1/2.
IPR015940. UBA.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF037014. Ser/Thr_PK_SNF1-like. 1 hit.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50030. UBA. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9R1U5-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVIMSEFSAV PTGTGQGQQK PLRVGFYDVE RTLGKGNFAV VKLARHRVTK
60 70 80 90 100
TQVAIKIIDK TRLDSSNLEK IYREVQLMKL LNHPNIIKLY QVMETKDMLY
110 120 130 140 150
IVTEFAKNGE MFDYLTSNGH LSENEARKKF WQILSAVEYC HNHHIVHRDL
160 170 180 190 200
KTENLLLDGN MDIKLADFGF GNFYKPGEPL STWCGSPPYA APEVFEGKEY
210 220 230 240 250
EGPQLDIWSL GVVLYVLVCG SLPFDGPNLP TLRQRVLEGR FRIPFFMSQD
260 270 280 290 300
CETLIRRMLV VDPAKRITIA QIRQHRWMQA DPTLLQQDDP AFSMQGYTSN
310 320 330 340 350
LGDYNEQVLG IMQALGIDRQ RTVESLQNSS YNHFAAIYYL LLERLREHRS
360 370 380 390 400
TQPSSRATPA PARQPQLRNS DLSSLEVPQE ILPCDPFRPS LLCPQPQALA
410 420 430 440 450
QSVLQAEIDC DLHSSLQPLF FPLDTNCSGV FRHRSISPSS LLDTAISEEA
460 470 480 490 500
RQGPSLEEEQ EVQEPLPGST GRRHTLAEVS THFSPLNPPC IIVSSSAAVS
510 520 530 540 550
PSEGTSSDSC LPFSASEGPA GLGGGLATPG LLGTSSPVRL ASPFLGSQSA
560 570 580 590 600
TPVLQSQAGL GATVLPPVSF QEGRRASDTS LTQGLKAFRQ QLRKNARTKG
610 620 630 640 650
FLGLNKIKGL ARQVCQSSIR GSRGGMSTFH TPAPSSGLQG CTASSREGRS
660 670 680 690 700
LLEEVLHQQR LLQLQHHSAV SSDYQQAPQL SPVPYVLTPC DGLLVSGIPL
710 720 730 740 750
LPTPLLQPGM SPVASAAQLL DAHLHISAGP VALPTGPLPQ CLTRLSPSCD
760 770
PAGLPQGDCE MEDLTSGQRG TFVLVQ
Length:776
Mass (Da):84,909
Last modified:May 1, 2000 - v1
Checksum:i7BF745AF28F17E6E
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti473 – 4731R → K in AAF14191 (PubMed:10820182).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB020480 mRNA. Translation: BAA82673.1.
AF106937 mRNA. Translation: AAF14191.1.
RefSeqiNP_067725.2. NM_021693.2.
UniGeneiRn.42905.

Genome annotation databases

EnsembliENSRNOT00000001579; ENSRNOP00000001579; ENSRNOG00000001189.
GeneIDi59329.
KEGGirno:59329.
UCSCiRGD:69407. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB020480 mRNA. Translation: BAA82673.1.
AF106937 mRNA. Translation: AAF14191.1.
RefSeqiNP_067725.2. NM_021693.2.
UniGeneiRn.42905.

3D structure databases

ProteinModelPortaliQ9R1U5.
SMRiQ9R1U5. Positions 24-341.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-46210N.
STRINGi10116.ENSRNOP00000001579.

PTM databases

iPTMnetiQ9R1U5.
PhosphoSiteiQ9R1U5.

Proteomic databases

PaxDbiQ9R1U5.
PRIDEiQ9R1U5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000001579; ENSRNOP00000001579; ENSRNOG00000001189.
GeneIDi59329.
KEGGirno:59329.
UCSCiRGD:69407. rat.

Organism-specific databases

CTDi150094.
RGDi69407. Sik1.

Phylogenomic databases

eggNOGiKOG0586. Eukaryota.
ENOG410XNQ0. LUCA.
GeneTreeiENSGT00790000122947.
HOGENOMiHOG000039981.
InParanoidiQ9R1U5.
KOiK19008.
OMAiPPCIVVS.
OrthoDBiEOG70ZZMM.
PhylomeDBiQ9R1U5.
TreeFamiTF315213.

Miscellaneous databases

PROiQ9R1U5.

Gene expression databases

GenevisibleiQ9R1U5. RN.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
IPR017090. Ser/Thr_kinase_SIK1/2.
IPR015940. UBA.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF037014. Ser/Thr_PK_SNF1-like. 1 hit.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50030. UBA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet-treated rat adrenal."
    Wang Z., Takemori H., Halder S.K., Nonaka Y., Okamoto M.
    FEBS Lett. 453:135-139(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], AUTOPHOSPHORYLATION, INDUCTION.
    Strain: Sprague-Dawley.
    Tissue: Adrenal gland.
  2. "The salt-inducible kinase, SIK, is induced by depolarization in brain."
    Feldman J.D., Vician L., Crispino M., Hoe W., Baudry M., Herschman H.R.
    J. Neurochem. 74:2227-2238(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INDUCTION.
  3. "SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process."
    Sjostrom M., Stenstrom K., Eneling K., Zwiller J., Katz A.I., Takemori H., Bertorello A.M.
    Proc. Natl. Acad. Sci. U.S.A. 104:16922-16927(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF PPME1, PHOSPHORYLATION AT THR-322, MUTAGENESIS OF THR-322, INTERACTION WITH ATP1A1.
  4. "Inactivation of HDAC5 by SIK1 in AICAR-treated C2C12 myoblasts."
    Takemori H., Katoh Hashimoto Y., Nakae J., Olson E.N., Okamoto M.
    Endocr. J. 56:121-130(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  5. "TORC1 regulates activity-dependent CREB-target gene transcription and dendritic growth of developing cortical neurons."
    Li S., Zhang C., Takemori H., Zhou Y., Xiong Z.Q.
    J. Neurosci. 29:2334-2343(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF CRTC1, SUBCELLULAR LOCATION.

Entry informationi

Entry nameiSIK1_RAT
AccessioniPrimary (citable) accession number: Q9R1U5
Secondary accession number(s): Q9R081
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: May 1, 2000
Last modified: June 8, 2016
This is version 133 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.