A4K2Q5 (STK4_OTOGA) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase 4
EC=2.7.11.1

Cleaved into the following 2 chains:

1. Serine/threonine-protein kinase 4 37kDa subunit
   Short name=MST1/N
2. Serine/threonine-protein kinase 4 18kDa subunit
   Short name=MST1/C

Gene names

Name:

STK4

Organism

Otolemur garnettii (Small-eared galago) (Garnett's greater bushbaby) [Reference proteome]

Taxonomic identifier

30611 [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 › Strepsirrhini › Lorisiformes › Galagidae › Otolemur

Protein attributes

Sequence length	487 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 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes By similarity.
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-183. 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 RASSF1. Interacts with FOXO3. Interacts with RASSF2 (via SARAH domain). Interacts with AR, PKB/AKT1, TNNI3 and SIRT1 By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: The caspase-cleaved form cycles between the nucleus and cytoplasm By similarity.
Post-translational modification	Autophosphorylated on serine and threonine residues. Phosphorylation at Thr-120 and Thr-387 by PKB/AKT1, leads to inhibition of its: kinase activity, nuclear translocation and autophosphorylation at Thr-183. It also diminishes its cleavage by caspases and its ability to phosphorylate FOXO3 By similarity. Proteolytically cleaved by caspase-3 during apoptosis at Asp-326 and Asp-349 resulting in a 37 kDa or a 39 kDa subunit respectively. The 39 kDa subunit is further cleaved into the 37 kDa form. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N). It is less likely that cleavage at Asp-349 is a prerequisite for activation as this site is not conserved in the murine ortholog By similarity.
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.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Nucleus
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 electronic annotation. Source: Compara cell morphogenesis Inferred from electronic annotation. Source: Compara central nervous system development Inferred from electronic annotation. Source: Compara endocardium development Inferred from electronic annotation. Source: Compara hippo signaling cascade Inferred from sequence or structural similarity. Source: UniProtKB induction of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB intracellular protein kinase cascade Inferred from electronic annotation. Source: Compara keratinocyte differentiation Inferred from electronic annotation. Source: Compara negative regulation of canonical Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of organ growth Inferred from electronic annotation. Source: Compara neural tube formation Inferred from electronic annotation. Source: Compara patterning of blood vessels Inferred from electronic annotation. Source: Compara peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara primitive hemopoiesis Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: Compara 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...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 487	487	Serine/threonine-protein kinase 4		PRO_0000289625
	Chain	1 – 326	326	Serine/threonine-protein kinase 4 37kDa subunit By similarity		PRO_0000413743
	Chain	327 – 487	161	Serine/threonine-protein kinase 4 18kDa subunit By similarity		PRO_0000413744
Regions
	Domain	30 – 281	252	Protein kinase
	Domain	433 – 480	48	SARAH
	Nucleotide binding	36 – 44	9	ATP By similarity
	Coiled coil	290 – 310	21	Potential
Sites
	Active site	149	1	Proton acceptor By similarity
	Binding site	59	1	ATP By similarity
	Site	326 – 327	2	Cleavage; by caspase-3 By similarity
	Site	349 – 350	2	Cleavage; by caspase-3 By similarity
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine By similarity
	Modified residue	3	1	Phosphothreonine By similarity
	Modified residue	120	1	Phosphothreonine; by PKB/AKT1 By similarity
	Modified residue	183	1	Phosphothreonine; by autocatalysis
	Modified residue	265	1	Phosphoserine By similarity
	Modified residue	320	1	Phosphoserine By similarity
	Modified residue	340	1	Phosphothreonine By similarity
	Modified residue	367	1	Phosphothreonine By similarity
	Modified residue	387	1	Phosphothreonine; by PKB/AKT1 By similarity
	Modified residue	410	1	Phosphoserine By similarity
	Modified residue	414	1	Phosphoserine By similarity
	Modified residue	433	1	Phosphotyrosine By similarity

Sequences

	Sequence		Length	Mass (Da)
	A4K2Q5 [UniParc]. Last modified May 1, 2007. Version 1. Checksum: AA973C056C5B5B82	FASTA	487	55,540
	10 20 30 40 50 60 METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK ETGQIVAIKQ 70 80 90 100 110 120 VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI VMEYCGAGSV SDIIRLRNKT 130 140 150 160 170 180 LTEDEIATIL QSTLKGLEYL HFMRKIHRDI KAGNILLNTE GHAKLADFGV AGQLTDTMAK 190 200 210 220 230 240 RNTVIGTPFW MAPEVIQEIG YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP 250 260 270 280 290 300 PPTFRKPELW SDNFTDFVRQ CLVKSPDQRA TATQLLQHPF VKSAKGVSIL RDLINEAMDV 310 320 330 340 350 360 KLKRQEAQQR EVDQDDEENS EEDELDSGTM VRAVGDEMGT VRVASTMSDG ANTMIEHDDT 370 380 390 400 410 420 LPSQLGTMVI NADDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK 430 440 450 460 470 480 NSSDWKVPQD GDYEFLKSWT VEDLQKRLLA LDPMMEQEIE EIRQKYQSKR QPILDAIEAK KRRQQNF

References

[1]	"Comparative sequence analyses reveal rapid and divergent evolutionary changes of the WFDC locus in the primate lineage." NISC comparative sequencing program Hurle B., Swanson W., Green E.D. Genome Res. 17:276-286(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].

Cross-references

Sequence databases
EMBL GenBank DDBJ	DP000040 Genomic DNA. Translation: ABO52940.1.
RefSeq	XP_003787676.1. XM_003787628.1.
3D structure databases
ProteinModelPortal	A4K2Q5.
SMR	A4K2Q5. Positions 16-300, 431-480.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSOGAT00000006659; ENSOGAP00000005955; ENSOGAG00000006656.
GeneID	100959420.
Organism-specific databases
CTD	6789.
Phylogenomic databases
GeneTree	ENSGT00640000091192.
HOVERGEN	HBG108518.
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...

Entry information

Entry name

STK4_OTOGA

Accession

Primary (citable) accession number: A4K2Q5

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 29, 2007
Last sequence update:	May 1, 2007
Last modified:	May 1, 2013
This is version 44 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program