A4K2Q5 (STK4_OTOGA) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 44. History...
Names and origin
|Protein names||Recommended name:|
Serine/threonine-protein kinase 4
|Organism||Otolemur garnettii (Small-eared galago) (Garnett's greater bushbaby) [Reference proteome]|
|Taxonomic identifier||30611 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Strepsirrhini › Lorisiformes › Galagidae › Otolemur|
|Sequence length||487 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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.
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
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.
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.
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.
Contains 1 protein kinase domain.
Contains 1 SARAH domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|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|
|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|
|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|
|DP000040 Genomic DNA. Translation: ABO52940.1.|
|RefSeq||XP_003787676.1. XM_003787628.1. |
3D structure databases
|SMR||A4K2Q5. Positions 16-300, 431-480. |
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSOGAT00000006659; ENSOGAP00000005955; ENSOGAG00000006656. |
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF11629. Mst1_SARAH. 1 hit. |
PF00069. Pkinase. 1 hit.
|SMART||SM00220. S_TKc. 1 hit. |
|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.
|Accession||Primary (citable) accession number: A4K2Q5|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families