ID:STK4_HUMAN DESCRIPTION: RecName: Full=Serine/threonine-protein kinase 4; EC=2.7.11.1; AltName: Full=Mammalian STE20-like protein kinase 1; Short=MST-1; AltName: Full=STE20-like kinase MST1; AltName: Full=Serine/threonine-protein kinase Krs-2; Contains: RecName: Full=Serine/threonine-protein kinase 4 37kDa subunit; Short=MST1/N; Contains: RecName: Full=Serine/threonine-protein kinase 4 18kDa subunit; Short=MST1/C; 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. 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. SUBUNIT: 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. INTERACTION: Self; NbExp=3; IntAct=EBI-367376, EBI-367376; O95166:GABARAP; NbExp=2; IntAct=EBI-367376, EBI-712001; Q9H0R8:GABARAPL1; NbExp=2; IntAct=EBI-367376, EBI-746969; P60520:GABARAPL2; NbExp=2; IntAct=EBI-367376, EBI-720116; Q9GZQ8:MAP1LC3B; NbExp=7; IntAct=EBI-367376, EBI-373144; P35700:Prdx1 (xeno); NbExp=3; IntAct=EBI-367376, EBI-444948; Q9NS23-2:RASSF1; NbExp=4; IntAct=EBI-367376, EBI-438698; P50749:RASSF2; NbExp=4; IntAct=EBI-367376, EBI-960081; Q86WH2:RASSF3; NbExp=2; IntAct=EBI-367376, EBI-2845202; Q9H2L5:RASSF4; NbExp=3; IntAct=EBI-367376, EBI-2933362; Q8WWW0:RASSF5; NbExp=3; IntAct=EBI-367376, EBI-367390; Q8WWW0-2:RASSF5; NbExp=4; IntAct=EBI-367376, EBI-960502; Q8WWW0-3:RASSF5; NbExp=2; IntAct=EBI-367376, EBI-960507; Q6ZTQ3:RASSF6; NbExp=2; IntAct=EBI-367376, EBI-2933412; Q9H4B6:SAV1; NbExp=6; IntAct=EBI-367376, EBI-1017775; Q13188:STK3; NbExp=3; IntAct=EBI-367376, EBI-992580; Q91VJ4:Stk38 (xeno); NbExp=2; IntAct=EBI-367376, EBI-2527046; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=The caspase-cleaved form cycles between the nucleus and cytoplasm. TISSUE SPECIFICITY: Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Ubiquitously expressed. INDUCTION: Activity increases during mitosis. PTM: 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. PTM: 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. SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 SARAH domain. SEQUENCE CAUTION: Sequence=AAH29511.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence; Sequence=AAH58916.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/STK4ID42440ch20q11.html";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF03109 - ABC1 atypical kinase-like domain PF07714 - Protein tyrosine and serine/threonine kinase PF11629 - C terminal SARAH domain of Mst1 PF17667 - Fungal protein kinase
SCOP Domains: 47986 - DEATH domain 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on Q13043
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000902 cell morphogenesis GO:0001569 branching involved in blood vessel morphogenesis GO:0001841 neural tube formation GO:0001934 positive regulation of protein phosphorylation GO:0003157 endocardium development GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0007165 signal transduction GO:0007346 regulation of mitotic cell cycle GO:0007417 central nervous system development GO:0008285 negative regulation of cell proliferation GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0023014 signal transduction by protein phosphorylation GO:0030216 keratinocyte differentiation GO:0031098 stress-activated protein kinase signaling cascade GO:0032092 positive regulation of protein binding GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0035329 hippo signaling GO:0035556 intracellular signal transduction GO:0043065 positive regulation of apoptotic process GO:0045600 positive regulation of fat cell differentiation GO:0046621 negative regulation of organ growth GO:0046777 protein autophosphorylation GO:0050821 protein stabilization GO:0060215 primitive hemopoiesis GO:0060706 cell differentiation involved in embryonic placenta development GO:0060800 regulation of cell differentiation involved in embryonic placenta development GO:0071902 positive regulation of protein serine/threonine kinase activity GO:0090090 negative regulation of canonical Wnt signaling pathway GO:0097284 hepatocyte apoptotic process GO:1902043 positive regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1905461 positive regulation of vascular associated smooth muscle cell apoptotic process
AB209315 - Homo sapiens mRNA for serine/threonine kinase 4 variant protein. BC029511 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:5301283), partial cds. AK225326 - Homo sapiens mRNA for serine/threonine kinase 4 variant, clone: HEP10114. BC015332 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:4400771), partial cds. BC038850 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:5141115), with apparent retained intron. CR933633 - Homo sapiens mRNA; cDNA DKFZp686A2068 (from clone DKFZp686A2068). BC093768 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone MGC:120803 IMAGE:7939613), complete cds. AK315238 - Homo sapiens cDNA, FLJ96240, Homo sapiens serine/threonine kinase 4 (STK4), mRNA. U60207 - Homo sapiens serine/threonine protein kinase Krs-2 mRNA, complete cds. BC058916 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:4390245), partial cds. U18297 - Human MST1 (MST1) mRNA, complete cds. AK309169 - Homo sapiens cDNA, FLJ99210. BC005231 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:3950315), complete cds. BC039023 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:6095545), with apparent retained intron. KJ901769 - Synthetic construct Homo sapiens clone ccsbBroadEn_11163 STK4 gene, encodes complete protein. Z25430 - H.sapiens protein-serine/threonine kinase gene, complete CDS. AY227114 - Homo sapiens kinase/transmembrane domain fusion protein (STK4/SLC36AL fusion) mRNA, partial cds. JD184970 - Sequence 165994 from Patent EP1572962. JD293773 - Sequence 274797 from Patent EP1572962. JD499278 - Sequence 480302 from Patent EP1572962. JD418290 - Sequence 399314 from Patent EP1572962. JD479181 - Sequence 460205 from Patent EP1572962. JD280289 - Sequence 261313 from Patent EP1572962. JD349206 - Sequence 330230 from Patent EP1572962. BC065215 - Homo sapiens cDNA clone IMAGE:5103522, partial cds. JD552600 - Sequence 533624 from Patent EP1572962. DQ587077 - Homo sapiens piRNA piR-54189, complete sequence. DQ590765 - Homo sapiens piRNA piR-57877, complete sequence. JD536913 - Sequence 517937 from Patent EP1572962. JD082011 - Sequence 63035 from Patent EP1572962. AK027088 - Homo sapiens cDNA: FLJ23435 fis, clone HRC12631. BC042861 - Homo sapiens serine/threonine kinase 4, mRNA (cDNA clone IMAGE:5269433). JD523052 - Sequence 504076 from Patent EP1572962. JD513585 - Sequence 494609 from Patent EP1572962. JD257493 - Sequence 238517 from Patent EP1572962. JD219925 - Sequence 200949 from Patent EP1572962. JD219924 - Sequence 200948 from Patent EP1572962. JD183062 - Sequence 164086 from Patent EP1572962.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein Q13043 (Reactome details) participates in the following event(s):
R-HSA-2028692 Cleavage of p-STK4 (p-MST1) by caspase 3 R-HSA-2028284 Phosphorylation of STK4 (MST1) and SAV1 by STK4 R-HSA-2028555 Phosphorylation of LATS1 and 2 by p-STK4 (p-MST1) R-HSA-2028629 Phosphorylation of MOB1A and B by p-STK4 (p-MST1) R-HSA-2028670 Phosphorylation of MOB1A and B by p-STK4(MST1)/N R-HSA-2028679 Phosphorylation of LATS1 and 2 by p-STK4(MST1)/N R-HSA-2028269 Signaling by Hippo R-HSA-162582 Signal Transduction
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
