Q60670 (SIK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	779 AA.
Sequence status	Complete.
Protein existence	Evidence 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.10 Ref.11 Ref.12
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 process	Cell cycle Differentiation
Cellular component	Cytoplasm Nucleus
Disease	Tumor suppressor
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	anoikis Inferred from mutant phenotype Ref.10. Source: BHF-UCL cardiac muscle cell differentiation Inferred from mutant phenotype Ref.12. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW intracellular protein kinase cascade 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: Compara negative regulation of triglyceride biosynthetic process Inferred from direct assay Ref.11. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity. 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_component	cytoplasm Inferred from direct assay Ref.3Ref.5Ref.7. Source: UniProtKB cytosol Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay Ref.3Ref.7. Source: UniProtKB
Molecular_function	14-3-3 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 magnesium ion binding Inferred from direct assay Ref.5. Source: UniProtKB protein serine/threonine kinase activity Inferred from direct assay Ref.5Ref.6Ref.8Ref.11. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 779	779	Serine/threonine-protein kinase SIK1		PRO_0000086660
Regions
	Domain	27 – 278	252	Protein kinase
	Domain	303 – 343	41	UBA
	Nucleotide binding	33 – 41	9	ATP By similarity
	Region	586 – 612	27	RK-rich region
Sites
	Active site	149	1	Proton acceptor By similarity
	Binding site	56	1	ATP
Amino acid modifications
	Modified residue	182	1	Phosphothreonine; by LKB1 and GSK3-beta Ref.7
	Modified residue	186	1	Phosphoserine; by autocatalysis By similarity
	Modified residue	322	1	Phosphothreonine; by CaMK1 By similarity
	Modified residue	577	1	Phosphoserine; by PKA Ref.3 Ref.7 Ref.8 Ref.9
Experimental info
	Mutagenesis	56	1	K → M: Loss of kinase activity. Ref.5 Ref.7 Ref.8
	Mutagenesis	182	1	T → A: Loss of kinase activity. Ref.7
	Mutagenesis	182	1	T → E: Low levels of constitutive activity. Ref.7
	Mutagenesis	268	1	T → A: Does not affect phosphorylation by PKA and nuclear export following ACTH treatment. Ref.3
	Mutagenesis	475	1	T → A: Does not affect phosphorylation by PKA and nuclear export following ACTH treatment. Ref.3
	Mutagenesis	577	1	S → A: Abolishes phosphorylation by PKA and impairs nuclear export following ACTH treatment. Ref.3 Ref.7 Ref.8
	Mutagenesis	577	1	S → A: Constitutively active. Ref.3 Ref.7 Ref.8
	Mutagenesis	593 – 594	2	RK → AA: Localizes mainly in cytoplasm and not in nucleus.
	Mutagenesis	597 – 599	3	RTK → ATA: Localizes mainly in cytoplasm and not in nucleus. Ref.4
	Mutagenesis	606 – 608	3	KIK → AIA: Localizes mainly in cytoplasm and not in nucleus. Ref.4
	Mutagenesis	607	1	I → A: Localizes mainly in cytoplasm and not in nucleus; when associated with D-483 and A-610. Ref.4
	Mutagenesis	610	1	L → A: Localizes mainly in cytoplasm and not in nucleus; when associated with D-483 and A-607. Ref.4
	Sequence conflict	183 – 184	2	WC → CV in AAA67926. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q60670 [UniParc]. Last modified October 19, 2011. Version 3. Checksum: 9C4D25CCF0C0D06D	FASTA	779	85,115
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-577, MASS SPECTROMETRY. Tissue: Melanoma.
[10]	"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.
[11]	"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.
[12]	"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.
IPI	IPI00331743.
PIR	I49072.
RefSeq	NP_034961.2. NM_010831.2.
UniGene	Mm.290941.
3D structure databases
ProteinModelPortal	Q60670.
SMR	Q60670. Positions 24-341.
ModBase	Search...
PTM databases
PhosphoSite	Q60670.
Proteomic databases
PRIDE	Q60670.
Protocols and materials databases
DNASU	17691.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000024839; ENSMUSP00000024839; ENSMUSG00000024042.
GeneID	17691.
KEGG	mmu:17691.
UCSC	uc008bvr.1. mouse.
Organism-specific databases
CTD	150094.
MGI	MGI:104754. Sik1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00700000104365.
HOGENOM	HOG000039981.
InParanoid	Q60670.
KO	K16311.
OMA	STGRRHT.
OrthoDB	EOG42FSH2.
Gene expression databases
ArrayExpress	Q60670.
Bgee	Q60670.
CleanEx	MM_SNF1LK.
Genevestigator	Q60670.
GermOnline	ENSMUSG00000024042. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_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]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
PIRSF	PIRSF037014. Ser/Thr_PK_SNF1-like. 1 hit.
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS50030. UBA. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	292274.
SOURCE	Search...

Entry information

Entry name

SIK1_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 119 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program