Protein: Serine/threonine-protein kinase 4 (EC 2.7.11.1) (Mammalian STE20-like protein kinase 1) (MST-1) (STE20-like kinase MST1) (Serine/threonine-protein kinase Krs-2) [Cleaved into: Serine/threonine-protein kinase 4 37kDa subunit (MST1/N); Serine/threonine-protein kinase 4 18kDa subunit (MST1/C)] (Q13043)
Organism: Homo sapiens (Human)
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.
Subcellular location: Cytoplasm. Nucleus. Note=The caspase-cleaved form cycles between the nucleus and cytoplasm.
Sequence: METVQLRNPPRRQLKKLDEDSLTKQPEEVFDVLEKLGEGSYGSVYKAIHKETGQIVAIKQVPVESDLQEIIKEISIMQQCDSPHVVKYYGSYFKNTDLWIVMEYCGAGSVSDIIRLRNKTLTEDEIATILQSTLKGLEYLHFMRKIHRDIKAGNILLNTEGHAKLADFGVAGQLTDTMAKRNTVIGTPFWMAPEVIQEIGYNCVADIWSLGITAIEMAEGKPPYADIHPMRAIFMIPTNPPPTFRKPELWSDNFTDFVKQCLVKSPEQRATATQLLQHPFVRSAKGVSILRDLINEAMDVKLKRQESQQREVDQDDEENSEEDEMDSGTMVRAVGDEMGTVRVASTMTDGANTMIEHDDTLPSQLGTMVINAEDEEEEGTMKRRDETMQPAKPSFLEYFEQKEKENQINSFGKSVPGPLKNSSDWKIPQDGDYEFLKSWTVEDLQKRLLALDPMMEQEIEEIRQKYQSKRQPILDAIEAKKRRQQNF
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [27-285]
- IPR024205: Mst1/2 SARAH domain (domain) [433-480]
- IPR011524: SARAH domain (domain) [433-480]
- IPR050629: STE20/SPS1-related Proline-Alanine-rich Kinase (family) [22-413]
- IPR017441: Protein kinase, ATP binding site (binding_site) [36-59]
- IPR000719: Protein kinase domain (domain) [30-281]
- IPR036674: p53-like tetramerisation domain superfamily (homologous_superfamily) [431-487]
Interaction partners: - Protein salvador homolog 1
- Ras association domain-containing protein 5
- MOB kinase activator 1A
- Ras association domain-containing protein 1
- Serine/threonine-protein kinase 3
- Forkhead box protein O3
- Serine/threonine-protein kinase LATS2
- Ras association domain-containing protein 2
- Forkhead box protein O1
- Caspase-3
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005515 (protein binding)
Biological Process (BP): GO:0008150 (biological process), GO:0065007 (biological regulation), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0048519 (negative regulation of biological process), GO:0050793 (regulation of developmental process), GO:0023057 (negative regulation of signaling), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0023051 (regulation of signaling), GO:0051241 (negative regulation of multicellular organismal process), GO:0051239 (regulation of multicellular organismal process), GO:0051094 (positive regulation of developmental process), GO:0051093 (negative regulation of developmental process), GO:0048523 (negative regulation of cellular process), GO:0048585 (negative regulation of response to stimulus), GO:0048522 (positive regulation of cellular process), GO:0045597 (positive regulation of cell differentiation), GO:0009968 (negative regulation of signal transduction), GO:0010648 (negative regulation of cell communication), GO:2000026 (regulation of multicellular organismal development), GO:0010646 (regulation of cell communication), GO:0045596 (negative regulation of cell differentiation), GO:0009966 (regulation of signal transduction), GO:0045595 (regulation of cell differentiation), GO:0051962 (positive regulation of nervous system development), GO:1901343 (negative regulation of vasculature development), GO:0045746 (negative regulation of Notch signaling pathway), GO:0008593 (regulation of Notch signaling pathway), GO:0060284 (regulation of cell development), GO:0010720 (positive regulation of cell development), GO:0050769 (positive regulation of neurogenesis), GO:0051960 (regulation of nervous system development), GO:0010721 (negative regulation of cell development), GO:0030336 (negative regulation of cell migration), GO:1902692 (regulation of neuroblast proliferation), GO:0050767 (regulation of neurogenesis), GO:0007406 (negative regulation of neuroblast proliferation)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005829 (cytosol), GO:0005737 (cytoplasm), GO:0031974 (membrane-enclosed lumen), GO:0016604 (nuclear body), GO:0005654 (nucleoplasm), GO:0043233 (organelle lumen), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)