Q13043 (STK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Alternative name(s):
Mammalian STE20-like protein kinase 1
Short name=MST-1
STE20-like kinase MST1
Serine/threonine-protein kinase Krs-2

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
Synonyms:	KRS2, MST1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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 By similarity. 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. Ref.2 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.19 Ref.23 Ref.25 Ref.29 Ref.30 Ref.32
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
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. Ref.8 Ref.12 Ref.31
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. Ref.8 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.23 Ref.25 Ref.30 Ref.31 Ref.32
Subcellular location	Cytoplasm. Nucleus. Note: The caspase-cleaved form cycles between the nucleus and cytoplasm. Ref.9 Ref.10 Ref.16 Ref.25 Ref.30
Tissue specificity	Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Ubiquitously expressed. Ref.16
Induction	Activity increases during mitosis. Ref.8 Ref.12 Ref.31
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. Ref.11 Ref.12 Ref.17 Ref.18 Ref.20 Ref.21 Ref.24 Ref.26 Ref.27 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. Ref.9
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 AAH29511.1 differs from that shown. Reason: Contaminating sequence. Potential poly-A sequence. The sequence AAH58916.1 differs from that shown. Reason: Contaminating sequence. Potential poly-A sequence.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Coiled coil
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cell morphogenesis Inferred from direct assay. Source: MGI hippo signaling cascade Traceable author statement Ref.22. Source: UniProtKB induction of apoptosis Inferred from direct assay Ref.32. Source: UniProtKB intracellular protein kinase cascade Inferred from direct assay. Source: UniProtKB negative regulation of canonical Wnt receptor signaling pathway Inferred from mutant phenotype. Source: BHF-UCL peptidyl-serine phosphorylation Inferred from direct assay Ref.14. Source: UniProtKB protein autophosphorylation Inferred from direct assay. Source: MGI
Cellular component	cytoplasm Inferred from direct assay Ref.16Ref.25Ref.30. Source: UniProtKB nucleus Inferred from direct assay Ref.16Ref.30. Source: UniProtKB
Molecular function	ATP binding Inferred from direct assay. Source: UniProtKB magnesium ion binding Inferred from direct assay. Source: UniProtKB protein homodimerization activity Inferred from direct assay. Source: MGI protein serine/threonine kinase activator activity Inferred from direct assay. Source: BHF-UCL protein serine/threonine kinase activity Inferred from direct assay Ref.14Ref.19Ref.23Ref.25Ref.32Ref.30. Source: UniProtKB transcription factor binding Inferred from physical interaction Ref.14. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-367376,EBI-367376
GABARAP	O95166	2	EBI-367376,EBI-712001
GABARAPL1	Q9H0R8	2	EBI-367376,EBI-746969
GABARAPL2	P60520	2	EBI-367376,EBI-720116
MAP1LC3B	Q9GZQ8	7	EBI-367376,EBI-373144
RASSF1	Q9NS23-2	4	EBI-367376,EBI-438698
RASSF2	P50749	4	EBI-367376,EBI-960081
RASSF3	Q86WH2	2	EBI-367376,EBI-2845202
RASSF4	Q9H2L5	3	EBI-367376,EBI-2933362
RASSF5	Q8WWW0	3	EBI-367376,EBI-367390
RASSF5	Q8WWW0-2	4	EBI-367376,EBI-960502
RASSF5	Q8WWW0-3	2	EBI-367376,EBI-960507
RASSF6	Q6ZTQ3	2	EBI-367376,EBI-2933412
SAV1	Q9H4B6	6	EBI-367376,EBI-1017775
STK3	Q13188	3	EBI-367376,EBI-992580
Stk38	Q91VJ4	2	EBI-367376,EBI-2527046	From a different organism.

Alternative products

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

Isoform 1 (identifier: Q13043-1)

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: Q13043-2)

The sequence of this isoform differs from the canonical sequence as follows:
     436-462: LKSWTVEDLQKRLLALDPMMEQEIEEI → KTSQEQQSGKDICIQNCQGNLLCRYAF
     463-487: Missing.

Note: No experimental confirmation available.

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_0000086691

Chain

1 – 326

326

Serine/threonine-protein kinase 4 37kDa subunit

PRO_0000413735

Chain

327 – 487

161

Serine/threonine-protein kinase 4 18kDa subunit

PRO_0000413736

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

Compositional bias

373 – 378

6

Poly-Glu

Sites

Active site

149

1

Proton acceptor By similarity

Binding site

59

1

ATP

Site

326 – 327

2

Cleavage; by caspase-3

Site

349 – 350

2

Cleavage; by caspase-3

Amino acid modifications

Modified residue

1

1

N-acetylmethionine Ref.7

Modified residue

3

1

Phosphothreonine Ref.24

Modified residue

40

1

Phosphoserine Ref.24

Modified residue

41

1

Phosphotyrosine Ref.24

Modified residue

120

1

Phosphothreonine; by PKB/AKT1 Ref.27

Modified residue

175

1

Phosphothreonine Ref.24

Modified residue

177

1

Phosphothreonine Ref.24

Modified residue

183

1

Phosphothreonine; by autocatalysis Ref.12

Modified residue

265

1

Phosphoserine Ref.20

Modified residue

320

1

Phosphoserine Ref.20 Ref.21 Ref.24 Ref.26

Modified residue

327

1

Phosphoserine Ref.24

Modified residue

329

1

Phosphothreonine Ref.24

Modified residue

340

1

Phosphothreonine Ref.20 Ref.24

Modified residue

353

1

Phosphothreonine Ref.24

Modified residue

360

1

Phosphothreonine Ref.24

Modified residue

367

1

Phosphothreonine Ref.24

Modified residue

380

1

Phosphothreonine Ref.24

Modified residue

387

1

Phosphothreonine; by PKB/AKT1 Ref.17 Ref.24

Modified residue

394

1

Phosphoserine Ref.24

Modified residue

410

1

Phosphoserine Ref.20 Ref.24

Modified residue

414

1

Phosphoserine Ref.24

Modified residue

422

1

Phosphoserine Ref.24

Modified residue

433

1

Phosphotyrosine Ref.18

Modified residue

438

1

Phosphoserine Ref.20 Ref.24

Natural variations

Alternative sequence

436 – 462

27

LKSWT…EIEEI → KTSQEQQSGKDICIQNCQGN LLCRYAF in isoform 2.

VSP_019851

Alternative sequence

463 – 487

25

Missing in isoform 2.

VSP_019852

Natural variant

162

1

H → N. [dbSNP:rs55850759] Ref.33

VAR_041123

Natural variant

310

1

R → Q. [dbSNP:rs35447878] Ref.33

VAR_041124

Natural variant

312

1

V → M. [dbSNP:rs17420378] Ref.1 Ref.33

VAR_027040

Natural variant

355

1

I → T. [dbSNP:rs35944046] Ref.33

VAR_041125

Natural variant

416

1

P → L. [dbSNP:rs33963346] Ref.33

VAR_041126

Experimental info

Mutagenesis

59

1

K → R: Loss of activity. Ref.12 Ref.15

Mutagenesis

175

1

T → A: No effect on activity. Ref.12

Mutagenesis

177

1

T → A: No effect on activity. Ref.12

Mutagenesis

183

1

T → A: Loss of activity. Ref.12

Mutagenesis

326

1

D → N: Resistant to proteolytic cleavage by caspase during apoptosis; when associated with N-349. Ref.9

Mutagenesis

349

1

D → N: Resistant to proteolytic cleavage by caspase during apoptosis; when associated with N-326. Ref.9

Mutagenesis

444

1

L → P: Loss of homodimerization, activation, and autophosphorylation. Ref.12

Sequence conflict

222

1

P → R in AAA83254. Ref.1

Secondary structure

1

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487

Helix Strand Turn

Details...

Helix

19 – 22

4

Beta strand

30 – 35

6

Beta strand

43 – 49

7

Turn

50 – 52

3

Beta strand

55 – 62

8

Helix

68 – 78

11

Beta strand

88 – 94

7

Beta strand

97 – 103

7

Helix

110 – 117

8

Helix

123 – 142

20

Helix

152 – 154

3

Beta strand

155 – 157

3

Beta strand

163 – 165

3

Helix

188 – 190

3

Helix

193 – 196

4

Beta strand

197 – 199

3

Helix

205 – 219

15

Turn

223 – 226

4

Helix

229 – 238

10

Helix

247 – 249

3

Helix

252 – 261

10

Turn

266 – 268

3

Helix

272 – 275

4

Helix

279 – 282

4

Helix

287 – 290

4

Helix

291 – 297

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 21, 2001. Version 2. Checksum: 150758EBC5F77D5C	FASTA	487	55,630
	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 SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VRSAKGVSIL RDLINEAMDV 310 320 330 340 350 360 KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT 370 380 390 400 410 420 LPSQLGTMVI NAEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK 430 440 450 460 470 480 NSSDWKIPQD GDYEFLKSWT VEDLQKRLLA LDPMMEQEIE EIRQKYQSKR QPILDAIEAK KRRQQNF
	Isoform 2 [UniParc]. Checksum: 9CFFF2D1FBC316E8	FASTA	462	52,335
	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 SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VRSAKGVSIL RDLINEAMDV 310 320 330 340 350 360 KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT 370 380 390 400 410 420 LPSQLGTMVI NAEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK 430 440 450 460 NSSDWKIPQD GDYEFKTSQE QQSGKDICIQ NCQGNLLCRY AF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a human protein kinase with homology to Ste20." Creasy C.L., Chernoff J. J. Biol. Chem. 270:21695-21700(1995) [PubMed: 7665586] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT MET-312.
[2]	"Newly identified stress-responsive protein kinases, Krs-1 and Krs-2." Taylor L.K., Wang H.C., Erikson R.L. Proc. Natl. Acad. Sci. U.S.A. 93:10099-10104(1996) [PubMed: 8816758] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
[3]	"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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[4]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone, Brain and Liver.
[7]	Bienvenut W.V., Matallanas D., Cooper W.N., Kolch W. Submitted (JUL-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 1-7; 16-94; 118-144; 152-181; 232-259; 270-282; 292-301; 333-342; 384-402; 405-413; 421-465 AND 470-481, ACETYLATION AT MET-1, MASS SPECTROMETRY. Tissue: Mammary carcinoma.
[8]	"The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain." Creasy C.L., Ambrose D.M., Chernoff J. J. Biol. Chem. 271:21049-21053(1996) [PubMed: 8702870] [Abstract] Cited for: FUNCTION, HOMODIMERIZATION, ENZYME REGULATION.
[9]	"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: 11278283] [Abstract] Cited for: FUNCTION, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-326 AND ASP-349.
[10]	"Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation." Ura S., Masuyama N., Graves J.D., Gotoh Y. Proc. Natl. Acad. Sci. U.S.A. 98:10148-10153(2001) [PubMed: 11517310] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[11]	"Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase." Cheung W.L., Ajiro K., Samejima K., Kloc M., Cheung P., Mizzen C.A., Beeser A., Etkin L.D., Chernoff J., Earnshaw W.C., Allis C.D. Cell 113:507-517(2003) [PubMed: 12757711] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF HISTONE H2B.
[12]	"Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras." Praskova M., Khoklatchev A., Ortiz-Vega S., Avruch J. Biochem. J. 381:453-462(2004) [PubMed: 15109305] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, HOMODIMERIZATION, PHOSPHORYLATION AT THR-183, MUTAGENESIS OF LYS-59; THR-175; THR-177; THR-183 AND LEU-444, INTERACTION WITH RASSF1 AND NORE1.
[13]	"Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis." Oh H.J., Lee K.-K., Song S.J., Jin M.S., Song M.S., Lee J.H., Im C.R., Lee J.-O., Yonehara S., Lim D.-S. Cancer Res. 66:2562-2569(2006) [PubMed: 16510573] [Abstract] Cited for: FUNCTION, INTERACTION WITH RASSF1.
[14]	"A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span." Lehtinen M.K., Yuan Z., Boag P.R., Yang Y., Villen J., Becker E.B.E., DiBacco S., de la Iglesia N., Gygi S.P., Blackwell T.K., Bonni A. Cell 125:987-1001(2006) [PubMed: 16751106] [Abstract] Cited for: FUNCTION, INTERACTION WITH FOXO3.
[15]	"Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation." Callus B.A., Verhagen A.M., Vaux D.L. FEBS J. 273:4264-4276(2006) [PubMed: 16930133] [Abstract] Cited for: INTERACTION WITH SAV1, FUNCTION, MUTAGENESIS OF LYS-59.
[16]	"The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1." Cinar B., Fang P.K., Lutchman M., Di Vizio D., Adam R.M., Pavlova N., Rubin M.A., Yelick P.C., Freeman M.R. EMBO J. 26:4523-4534(2007) [PubMed: 17932490] [Abstract] Cited for: FUNCTION, INTERACTION WITH PKB/AKT1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[17]	"Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation." Jang S.W., Yang S.J., Srinivasan S., Ye K. J. Biol. Chem. 282:30836-30844(2007) [PubMed: 17726016] [Abstract] Cited for: PHOSPHORYLATION AT THR-387, INTERACTION WITH PKB/AKT1.
[18]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-433, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[19]	"MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation." Praskova M., Xia F., Avruch J. Curr. Biol. 18:311-321(2008) [PubMed: 18328708] [Abstract] Cited for: FUNCTION.
[20]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-265; SER-320; THR-340; SER-410 AND SER-438, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[21]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[22]	"Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling." Hergovich A., Hemmings B.A. BioFactors 35:338-345(2009) [PubMed: 19484742] [Abstract] Cited for: REVIEW.
[23]	"Phosphorylation of cardiac troponin I by mammalian sterile 20-like kinase 1." You B., Yan G., Zhang Z., Yan L., Li J., Ge Q., Jin J.P., Sun J. Biochem. J. 418:93-101(2009) [PubMed: 18986304] [Abstract] Cited for: FUNCTION, INTERACTION WITH TNNI3.
[24]	"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: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-3; SER-40; TYR-41; THR-175; THR-177; SER-320; SER-327; THR-329; THR-340; THR-353; THR-360; THR-367; THR-380; THR-387; SER-394; SER-410; SER-414; SER-422 AND SER-438, MASS SPECTROMETRY.
[25]	"RASSF2 associates with and stabilizes the proapoptotic kinase MST2." Cooper W.N., Hesson L.B., Matallanas D., Dallol A., von Kriegsheim A., Ward R., Kolch W., Latif F. Oncogene 28:2988-2998(2009) [PubMed: 19525978] [Abstract] Cited for: FUNCTION, INTERACTION WITH RASSF2, SUBCELLULAR LOCATION.
[26]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[27]	"Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120." Yuan Z., Kim D., Shu S., Wu J., Guo J., Xiao L., Kaneko S., Coppola D., Cheng J.Q. J. Biol. Chem. 285:3815-3824(2010) [PubMed: 19940129] [Abstract] Cited for: PHOSPHORYLATION AT THR-120.
[28]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[29]	"Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner." Valis K., Prochazka L., Boura E., Chladova J., Obsil T., Rohlena J., Truksa J., Dong L.F., Ralph S.J., Neuzil J. Cancer Res. 71:946-954(2011) [PubMed: 21245099] [Abstract] Cited for: FUNCTION.
[30]	"MST1 is a multifunctional caspase-independent inhibitor of androgenic signaling." Cinar B., Collak F.K., Lopez D., Akgul S., Mukhopadhyay N.K., Kilicarslan M., Gioeli D.G., Freeman M.R. Cancer Res. 71:4303-4313(2011) [PubMed: 21512132] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH AR.
[31]	"The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2." Guo C., Zhang X., Pfeifer G.P. J. Biol. Chem. 286:6253-6261(2011) [PubMed: 21199877] [Abstract] Cited for: INTERACTION WITH RASSF1, ENZYME REGULATION.
[32]	"MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation." Yuan F., Xie Q., Wu J., Bai Y., Mao B., Dong Y., Bi W., Ji G., Tao W., Wang Y., Yuan Z. J. Biol. Chem. 286:6940-6945(2011) [PubMed: 21212262] [Abstract] Cited for: FUNCTION, INTERACTION WITH SIRT1.
[33]	"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: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-162; GLN-310; MET-312; THR-355 AND LEU-416.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U18297 mRNA. Translation: AAA83254.1.
U60207 mRNA. Translation: AAB17262.1.
AK315238 mRNA. Translation: BAG37665.1.
Z93016, AL109839 Genomic DNA. Translation: CAB07508.2.
AL109839, Z93016 Genomic DNA. Translation: CAI95633.1.
AL109839, Z93016 Genomic DNA. Translation: CAI95634.1.
Z93016, AL109839 Genomic DNA. Translation: CAI19815.1.
CH471077 Genomic DNA. Translation: EAW75882.1.
BC029511 mRNA. Translation: AAH29511.1. Sequence problems.
BC058916 mRNA. Translation: AAH58916.1. Sequence problems.
BC093768 mRNA. Translation: AAH93768.1.

IPI

IPI00011488.
IPI00645585.

RefSeq

NP_006273.1. NM_006282.2.

UniGene

Hs.472838.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2JO8	NMR	-	A/B	432-480	[»]
3COM	X-ray	2.20	A/B	2-311	[»]

ProteinModelPortal

Q13043.

SMR

Q13043. Positions 16-300, 432-480.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-32491N.

IntAct

Q13043. 27 interactions.

MINT

MINT-4658525.

STRING

Q13043.

PTM databases

PhosphoSite

Q13043.

Polymorphism databases

DMDM

13124559.

Proteomic databases

PRIDE

Q13043.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000372806; ENSP00000361892; ENSG00000101109.

GeneID

6789.

KEGG

hsa:6789.

UCSC

uc002xnb.1. human.
uc010ggx.1. human.

Organism-specific databases

CTD

6789.

GeneCards

GC20P043595.

HGNC

HGNC:11408. STK4.

HPA

CAB004038.
HPA015270.

MIM

604965. gene.

neXtProt

NX_Q13043.

PharmGKB

PA36215.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

HBG108518.

InParanoid

Q13043.

OMA

KRRDETM.

OrthoDB

EOG4N30P2.

PhylomeDB

Q13043.

Enzyme and pathway databases

BRENDA

2.7.11.1. 2681.

Gene expression databases

ArrayExpress

Q13043.

Bgee

Q13043.

CleanEx

HS_MST1.
HS_STK4.

Genevestigator

Q13043.

GermOnline

ENSG00000101109. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR011524. SARAH.
IPR024205. SARAH_domain.
IPR017442. Se/Thr_kinase-like_dom.
IPR002290. Ser/Thr_kinase_dom.
[Graphical view]

KO

K04411.

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

NextBio

26508.

PMAP-CutDB

Q13043.

SOURCE

Search...

Entry information

Entry name

STK4_HUMAN

Accession

Primary (citable) accession number: Q13043
Secondary accession number(s): B2RCR8 , Q15802, Q4G156, Q5H982, Q6PD60, Q9BR32, Q9NTZ4

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 21, 2001
Last sequence update:	February 21, 2001
Last modified:	January 25, 2012
This is version 125 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.