Q9JI10 (STK3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase 3
EC=2.7.11.1

Alternative name(s):
Mammalian STE20-like protein kinase 2
Short name=MST-2
STE20-like kinase MST2

Cleaved into the following 2 chains:

1. Serine/threonine-protein kinase 3 36kDa subunit
   Short name=MST2/N
2. Serine/threonine-protein kinase 3 20kDa subunit
   Short name=MST2/C

Gene names

Name:	Stk3
Synonyms:	Mess1, Mst2

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	497 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1. Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38 By similarity. Ref.7
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-180, which are inhibited by the proto-oncogene product RAF1. Activated by RASSF1 which acts by preventing its dephosphorylation By similarity.
Subunit structure	Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RAF1, which prevents dimerization and phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain) with NEK2 By similarity. Interacts with ESR1 only in the presence of SAV1. Interacts with PKB/AKT1. Forms a tripartite complex with MOBKL1B and STK38. Interacts with RASSF2 (via SARAH domain) By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: The caspase-cleaved form cycles between nucleus and cytoplasm. Phosphorylation at Thr-117 leads to inhibition of nuclear translocation By similarity.
Post-translational modification	Phosphorylation at Thr-117 and Thr-390 by PKB/AKT1, leads to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation, and increase in its binding to RAF1 By similarity. Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N). Ref.1
Disruption phenotype	Mice show progressive hepatomegaly with a 2-fold increase in liver mass relative to total body mass at 1 month of age and a 3-fold increase by 3 months of age. Ref.7
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. Contains 1 protein kinase domain. Contains 1 SARAH domain.
Sequence caution	The sequence AAA75300.1 differs from that shown. Reason: Frameshift at position 432.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Coiled coil
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cell differentiation involved in embryonic placenta development Inferred from genetic interaction PubMed 19786569. Source: MGI central nervous system development Inferred from genetic interaction PubMed 19786569. Source: MGI endocardium development Inferred from genetic interaction PubMed 19786569. Source: MGI hippo signaling cascade Inferred from mutant phenotype Ref.7. Source: UniProtKB intracellular protein kinase cascade Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of canonical Wnt receptor signaling pathway Inferred from genetic interaction PubMed 20080598. Source: MGI negative regulation of cell proliferation Inferred from genetic interaction PubMed 19786569PubMed 20080598. Source: MGI negative regulation of organ growth Inferred from genetic interaction PubMed 20080598. Source: MGI neural tube formation Inferred from genetic interaction PubMed 19786569. Source: MGI positive regulation of JNK cascade Inferred from genetic interaction PubMed 20080598. Source: MGI positive regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein kinase B signaling cascade Inferred from genetic interaction PubMed 20080598. Source: MGI primitive hemopoiesis Inferred from genetic interaction PubMed 19786569. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay PubMed 11805089. Source: MGI nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from sequence or structural similarity. Source: UniProtKB magnesium ion binding Inferred from sequence or structural similarity. Source: UniProtKB protein dimerization activity Inferred from sequence or structural similarity. Source: UniProtKB protein serine/threonine kinase activator activity Inferred from electronic annotation. Source: Compara protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9JI10-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9JI10-2)

The sequence of this isoform differs from the canonical sequence as follows:
     9-78: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 497	497	Serine/threonine-protein kinase 3		PRO_0000086690
	Chain	1 – 322	322	Serine/threonine-protein kinase 3 36kDa subunit		PRO_0000413715
	Chain	323 – 497	175	Serine/threonine-protein kinase 3 20kDa subunit		PRO_0000413716
Regions
	Domain	27 – 278	252	Protein kinase
	Domain	443 – 490	48	SARAH
	Nucleotide binding	33 – 41	9	ATP By similarity
	Coiled coil	287 – 328	42	Potential
	Coiled coil	366 – 387	22	Potential
	Coiled coil	448 – 479	32	Potential
	Compositional bias	293 – 381	89	Glu-rich
	Compositional bias	308 – 314	7	Poly-Glu
	Compositional bias	370 – 381	12	Poly-Glu
Sites
	Active site	146	1	Proton acceptor By similarity
	Binding site	56	1	ATP By similarity
	Site	322 – 323	2	Cleavage; by caspase-3
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine By similarity
	Modified residue	15	1	Phosphoserine By similarity
	Modified residue	117	1	Phosphothreonine; by PKB/AKT1 By similarity
	Modified residue	180	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	316	1	Phosphoserine Ref.5 Ref.6
	Modified residue	336	1	Phosphothreonine By similarity
	Modified residue	390	1	Phosphothreonine; by PKB/AKT1 By similarity
	Modified residue	450	1	Phosphoserine By similarity
Natural variations
	Alternative sequence	9 – 78	70	Missing in isoform 2.		VSP_020047

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 2000. Version 1. Checksum: 9CDD365437581665	FASTA	497	56,855
	10 20 30 40 50 60 MEQPPASKSK LKKLSEDSLT KQPEEVFDVL EKLGEGSYGS VFKAIHKESG QVVAIKQVPV 70 80 90 100 110 120 ESDLQEIIKE ISIMQQCDSP YVVKYYGSYF KNTDLWIVME YCGAGSVSDI IRLRNKTLTE 130 140 150 160 170 180 DEIATILKST LKGLEYLHFM RKIHRDIKAG NILLNTEGHA KLADFGVAGQ LTDTMAKRNT 190 200 210 220 230 240 VIGTPFWMAP EVIQEIGYNC VADIWSLGIT SIEMAEGKPP YADIHPMRAI FMIPTNPPPT 250 260 270 280 290 300 FRKPELWSDD FTDFVKKCLV KSPEQRATAT QLLQHPFIKN AKPVSILRDL IAEAMEIKAK 310 320 330 340 350 360 RHEEQQRELE EEEENSDEDE LDSHTMVKTS SESVGTMRAT STMSEGAQTM IEHNSTMLES 370 380 390 400 410 420 DLGTMVINSE EEEEEEEEEE EDGTMKRNAT SPQVQRPSFM DYFDKQDFKN KSHENCDQSM 430 440 450 460 470 480 REPGPMSNSV FPDNWRVPQD GDFDFLKNLS LEELQMRLKA LDPMMEREIE ELHQRYSAKR 490 QPILDAMDAK KRRQQNF
	Isoform 2 [UniParc]. Checksum: 556176AE5A26F79E	FASTA	427	49,067
	10 20 30 40 50 60 MEQPPASKSP YVVKYYGSYF KNTDLWIVME YCGAGSVSDI IRLRNKTLTE DEIATILKST 70 80 90 100 110 120 LKGLEYLHFM RKIHRDIKAG NILLNTEGHA KLADFGVAGQ LTDTMAKRNT VIGTPFWMAP 130 140 150 160 170 180 EVIQEIGYNC VADIWSLGIT SIEMAEGKPP YADIHPMRAI FMIPTNPPPT FRKPELWSDD 190 200 210 220 230 240 FTDFVKKCLV KSPEQRATAT QLLQHPFIKN AKPVSILRDL IAEAMEIKAK RHEEQQRELE 250 260 270 280 290 300 EEEENSDEDE LDSHTMVKTS SESVGTMRAT STMSEGAQTM IEHNSTMLES DLGTMVINSE 310 320 330 340 350 360 EEEEEEEEEE EDGTMKRNAT SPQVQRPSFM DYFDKQDFKN KSHENCDQSM REPGPMSNSV 370 380 390 400 410 420 FPDNWRVPQD GDFDFLKNLS LEELQMRLKA LDPMMEREIE ELHQRYSAKR QPILDAMDAK KRRQQNF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation." Lee K.-K., Ohyama T., Yajima N., Tsubuki S., Yonehara S. J. Biol. Chem. 276:19276-19285(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEOLYTIC PROCESSING. Strain: BALB/c.
[2]	Han J. Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Liver.
[3]	"Molecular cloning and characterization of mouse MST2 kinase from olfactory receptor neurons." de las Heras R., Mackay-Sim A., Bushell G.R. Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Olfactory epithelium.
[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] (ISOFORMS 1 AND 2). Strain: C57BL/6 and FVB/N. Tissue: Brain and Mammary gland.
[5]	"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-316, MASS SPECTROMETRY. Tissue: Melanoma.
[6]	"The phagosomal proteome in interferon-gamma-activated macrophages." Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P. Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, MASS SPECTROMETRY. Tissue: Macrophage.
[7]	"Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver." Lu L., Li Y., Kim S.M., Bossuyt W., Liu P., Qiu Q., Wang Y., Halder G., Finegold M.J., Lee J.S., Johnson R.L. Proc. Natl. Acad. Sci. U.S.A. 107:1437-1442(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF271361 mRNA. Translation: AAF75790.1. U28726 mRNA. Translation: AAA75300.1. Frameshift. AY058922 mRNA. Translation: AAL29682.1. BC037440 mRNA. Translation: AAH37440.1. BC049123 mRNA. Translation: AAH49123.2.
IPI	IPI00474228. IPI00776074.
RefSeq	NP_062609.2. NM_019635.2.
UniGene	Mm.262330.
3D structure databases
ProteinModelPortal	Q9JI10.
SMR	Q9JI10. Positions 26-295, 442-490.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9JI10. 1 interaction.
PTM databases
PhosphoSite	Q9JI10.
Proteomic databases
PaxDb	Q9JI10.
PRIDE	Q9JI10.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000018476; ENSMUSP00000018476; ENSMUSG00000022329. ENSMUST00000067033; ENSMUSP00000064225; ENSMUSG00000022329.
GeneID	56274.
KEGG	mmu:56274.
UCSC	uc008ntt.1. mouse. uc011zrz.1. mouse.
Organism-specific databases
CTD	6788.
MGI	MGI:1928487. Stk3.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00640000091192.
HOGENOM	HOG000234203.
HOVERGEN	HBG108518.
InParanoid	Q9JI10.
KO	K04412.
OMA	MVKTSVE.
OrthoDB	EOG4N30P2.
Gene expression databases
ArrayExpress	Q9JI10.
Bgee	Q9JI10.
CleanEx	MM_STK3.
Genevestigator	Q9JI10.
GermOnline	ENSMUSG00000022329. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR024205. Mst1_SARAH_domain. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR011524. SARAH_dom. IPR002290. Ser/Thr_dual-sp_kinase_dom. [Graphical view]
Pfam	PF11629. Mst1_SARAH. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
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. False negative. PS50951. SARAH. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	Q9JI10.
ChEMBL	CHEMBL4310.
NextBio	312160.
SOURCE	Search...

Entry information

Entry name

STK3_MOUSE

Accession

Primary (citable) accession number: Q9JI10
Secondary accession number(s): Q60877, Q80UG4, Q8CI58

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 26, 2004
Last sequence update:	October 1, 2000
Last modified:	May 1, 2013
This is version 105 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program