P57059 (SIK1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase SIK1
EC=2.7.11.1

Alternative name(s):
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:	SIK, SNF1LK

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	783 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.1 Ref.6 Ref.7 Ref.9
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.1
Subunit structure	Interacts with ATP1A1 By similarity. Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ. Ref.6 Ref.7
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.6
Domain	The RK-rich region determines the subcellular location By similarity.
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-575 by PKA promotes translocation to the cytoplasm. Phosphorylation at Thr-322 by CaMK1 following intracellular sodium concentration leads to activation. Ref.1 Ref.7
Involvement in disease	Defects in SIK1 may be associated with some cancers, such as breast cancers. Loss of SIK1 correlates with poor patient outcome in breast cancers (Ref.9).
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
Coding sequence diversity	Polymorphism
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 electronic annotation. Source: Compara cardiac muscle cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW intracellular protein kinase cascade Inferred from direct assay Ref.1. Source: UniProtKB negative regulation of CREB transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of gluconeogenesis Inferred from sequence or structural similarity. 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 sequence or structural similarity. Source: UniProtKB positive regulation of anoikis Inferred from mutant phenotype Ref.9. Source: BHF-UCL protein autophosphorylation Inferred from direct assay Ref.7. Source: UniProtKB regulation of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB regulation of myotube differentiation Inferred from sequence or structural similarity. Source: UniProtKB regulation of sodium ion transport Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	cytoplasm Inferred from direct assay Ref.6. Source: UniProtKB cytosol Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay Ref.6. Source: UniProtKB
Molecular_function	14-3-3 protein binding Inferred from direct assay Ref.7. Source: UniProtKB ATP binding Inferred from direct assay Ref.1. Source: UniProtKB cAMP response element binding protein binding Inferred from sequence or structural similarity. Source: UniProtKB magnesium ion binding Inferred from direct assay Ref.1. Source: UniProtKB protein serine/threonine kinase activity Inferred from direct assay Ref.1Ref.7. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
YWHAZ	P63104	4	EBI-1181640,EBI-347088

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 783	783	Serine/threonine-protein kinase SIK1		PRO_0000086659
Regions
	Domain	27 – 278	252	Protein kinase
	Domain	303 – 343	41	UBA
	Nucleotide binding	33 – 41	9	ATP By similarity
	Region	584 – 610	27	RK-rich region By similarity
Sites
	Active site	149	1	Proton acceptor By similarity
	Binding site	56	1	ATP Probable
Amino acid modifications
	Modified residue	182	1	Phosphothreonine; by LKB1 and GSK3-beta Ref.1 Ref.7
	Modified residue	186	1	Phosphoserine; by autocatalysis Ref.7
	Modified residue	322	1	Phosphothreonine; by CaMK1 By similarity
	Modified residue	575	1	Phosphoserine; by PKA Probable
Natural variations
	Natural variant	15	1	G → S. Ref.10 Corresponds to variant rs3746951 [ dbSNP | Ensembl ].		VAR_041087
	Natural variant	142	1	D → N. Ref.10 Corresponds to variant rs45491503 [ dbSNP | Ensembl ].		VAR_041088
	Natural variant	211	1	G → S in a glioblastoma multiforme sample; somatic mutation. Ref.10		VAR_041089
	Natural variant	430	1	R → W. Corresponds to variant rs34164089 [ dbSNP | Ensembl ].		VAR_033910
	Natural variant	469	1	G → D in a metastatic melanoma sample; somatic mutation. Ref.10		VAR_041090
	Natural variant	615	1	A → V. Ref.4 Ref.5 Ref.10 Corresponds to variant rs430554 [ dbSNP | Ensembl ].		VAR_021255
	Natural variant	696	1	P → L. Ref.10 Corresponds to variant rs56386767 [ dbSNP | Ensembl ].		VAR_041091
	Natural variant	725	1	A → V. Ref.10 Corresponds to variant rs35596465 [ dbSNP | Ensembl ].		VAR_041092
Experimental info
	Mutagenesis	56	1	K → M: Loss of kinase activity. Ref.7 Ref.9
	Mutagenesis	135	1	S → A: Decreased kinase activity without affecting much autophosphorylation status. Ref.7
	Mutagenesis	182	1	T → A: Prevents phosphorylation and activation by STK11/LKB1 complex. Ref.1
	Mutagenesis	186	1	S → A, D, C or G: Impaired autophosphorylation and kinase activity. Ref.7
	Mutagenesis	186	1	S → T: Does not autophosphorylation and kinase activity. Ref.7
	Mutagenesis	209	1	S → A: Decreased kinase activity without affecting much autophosphorylation status. Ref.7
	Mutagenesis	248	1	S → A: Decreased kinase activity without affecting much autophosphorylation status. Ref.7
	Sequence conflict	166	1	A → AGTE in BAA95536. Ref.3
	Sequence conflict	489 – 490	2	IV → KF in BAA95536. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P57059 [UniParc]. Last modified February 15, 2005. Version 2. Checksum: D646123C0715DAAC	FASTA	783	84,902
	10 20 30 40 50 60 MVIMSEFSAD PAGQGQGQQK PLRVGFYDIE RTLGKGNFAV VKLARHRVTK TQVAIKIIDK 70 80 90 100 110 120 TRLDSSNLEK IYREVQLMKL LNHPHIIKLY QVMETKDMLY IVTEFAKNGE MFDYLTSNGH 130 140 150 160 170 180 LSENEARKKF WQILSAVEYC HDHHIVHRDL KTENLLLDGN MDIKLADFGF GNFYKSGEPL 190 200 210 220 230 240 STWCGSPPYA APEVFEGKEY EGPQLDIWSL GVVLYVLVCG SLPFDGPNLP TLRQRVLEGR 250 260 270 280 290 300 FRIPFFMSQD CESLIRRMLV VDPARRITIA QIRQHRWMRA EPCLPGPACP AFSAHSYTSN 310 320 330 340 350 360 LGDYDEQALG IMQTLGVDRQ RTVESLQNSS YNHFAAIYYL LLERLKEYRN AQCARPGPAR 370 380 390 400 410 420 QPRPRSSDLS GLEVPQEGLS TDPFRPALLC PQPQTLVQSV LQAEMDCELQ SSLQWPLFFP 430 440 450 460 470 480 VDASCSGVFR PRPVSPSSLL DTAISEEARQ GPGLEEEQDT QESLPSSTGR RHTLAEVSTR 490 500 510 520 530 540 LSPLTAPCIV VSPSTTASPA EGTSSDSCLT FSASKSPAGL SGTPATQGLL GACSPVRLAS 550 560 570 580 590 600 PFLGSQSATP VLQAQGGLGG AVLLPVSFQE GRRASDTSLT QGLKAFRQQL RKTTRTKGFL 610 620 630 640 650 660 GLNKIKGLAR QVCQAPASRA SRGGLSPFHA PAQSPGLHGG AAGSREGWSL LEEVLEQQRL 670 680 690 700 710 720 LQLQHHPAAA PGCSQAPQPA PAPFVIAPCD GPGAAPLPST LLTSGLPLLP PPLLQTGASP 730 740 750 760 770 780 VASAAQLLDT HLHIGTGPTA LPAVPPPRLA RLAPGCEPLG LLQGDCEMED LMPCSLGTFV LVQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1." Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A., Boudeau J., Hawley S.A., Udd L., Maekelae T.P., Hardie D.G., Alessi D.R. EMBO J. 23:833-843(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ENZYME REGULATION, PHOSPHORYLATION AT THR-182, MUTAGENESIS OF THR-182.
[2]	Shimizu N., Kudoh J., Shibuya K. Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal lung.
[3]	"The DNA sequence of human chromosome 21." Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A. , Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L. Nature 405:311-319(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-615. Tissue: Testis.
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 20-783, VARIANT VAL-615. Tissue: Spleen.
[6]	"14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK." Al-Hakim A.K., Goransson O., Deak M., Toth R., Campbell D.G., Morrice N.A., Prescott A.R., Alessi D.R. J. Cell Sci. 118:5661-5673(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH YWHAZ.
[7]	"Importance of autophosphorylation at Ser186 in the A-loop of salt inducible kinase 1 for its sustained kinase activity." Hashimoto Y.K., Satoh T., Okamoto M., Takemori H. J. Cell. Biochem. 104:1724-1739(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT THR-182 AND SER-186, INTERACTION WITH YWHAZ, MUTAGENESIS OF LYS-56; SER-135; SER-186; SER-209 AND SER-248.
[8]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[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, MUTAGENESIS OF LYS-56.
[10]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-15; ASN-142; SER-211; ASP-469; VAL-615; LEU-696 AND VAL-725.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB047786 mRNA. Translation: BAD74070.1. AP001751 Genomic DNA. Translation: BAA95536.1. BC038504 mRNA. Translation: AAH38504.1. AK131076 mRNA. Translation: BAC85126.1.
IPI	IPI00025679.
RefSeq	NP_775490.2. NM_173354.3.
UniGene	Hs.282113.
3D structure databases
ProteinModelPortal	P57059.
ModBase	Search...
Protein-protein interaction databases
IntAct	P57059. 6 interactions.
STRING	9606.ENSP00000270162.
PTM databases
PhosphoSite	P57059.
Polymorphism databases
DMDM	59803093.
Proteomic databases
PaxDb	P57059.
PRIDE	P57059.
Protocols and materials databases
DNASU	150094.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000270162; ENSP00000270162; ENSG00000142178.
GeneID	150094.
KEGG	hsa:150094.
UCSC	uc002zdf.2. human.
Organism-specific databases
CTD	150094.
GeneCards	GC21M044836.
HGNC	HGNC:11142. SIK1.
HPA	CAB023801.
MIM	605705. gene.
neXtProt	NX_P57059.
PharmGKB	PA164725717.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000039981.
InParanoid	P57059.
KO	K16311.
OMA	STGRRHT.
OrthoDB	EOG42FSH2.
Gene expression databases
Bgee	P57059.
Genevestigator	P57059.
GermOnline	ENSG00000142178. Homo sapiens.
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. SM00165. UBA. 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
BindingDB	P57059.
ChEMBL	CHEMBL6082.
ChiTaRS	SIK1. human.
GenomeRNAi	150094.
NextBio	86328.
SOURCE	Search...

Entry information

Entry name

SIK1_HUMAN

Accession

Primary (citable) accession number: P57059
Secondary accession number(s): A6NC84 , Q5R2V5, Q6ZNL8, Q86YJ2

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	February 15, 2005
Last modified:	May 1, 2013
This is version 131 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.