BioPAX pathway converted from "Phosphorylation of MOB1A and B by p-STK3 (p-MST2)" in the Reactome database. 2.7.11.1 Phosphorylation of MOB1A and B by p-STK3 (p-MST2) Phosphorylation of MOB1A and B by p-STK3 (p-MST2) Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK3 (p-MST2). Phosphorylated (active) STK3 (p-MST2) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Threonine residues 12 and 35 have been experimentally identifed as the targets of MOB1A phosphorylation; the homologous residues of MOB1B are inferred likewise to be targets (Praskova et al. 2008). Authored: D'Eustachio, P, 2012-02-03 Reviewed: Sudol, M, 2012-02-03 Edited: D'Eustachio, P, 2011-12-30 Reactome DB_ID: 113592 2 cytosol GO 0005829 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP Reactome http://www.reactome.org ChEBI 30616 Converted from EntitySet in Reactome Reactome DB_ID: 2028544 1 MOB1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MOB1A [cytosol] MOB1B [cytosol] Homo sapiens NCBI Taxonomy 9606 UniProt Q9H8S9 UniProt Q7L9L4 Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Converted from EntitySet in Reactome Reactome DB_ID: 2028620 1 p-MOB1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T12,T35-MOB1B [cytosol] p-T12,T35-MOB1A [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2028261 p-STK3:p-SAV1 [cytosol] p-STK3:p-SAV1 Reactome DB_ID: 2028281 1 p-SAV1 dimer [cytosol] p-SAV1 dimer phosphorylated salvador dimer Reactome DB_ID: 2028276 2 UniProt:Q9H4B6 SAV1 SAV1 WW45 SAV1 FUNCTION Regulator of STK3/MST2 and STK4/MST1 in 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 LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues. Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with STK3/MST2, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation.SUBUNIT Homodimer. Stabilized through interaction with STK3/MST2 or STK4/MST1. Interacts (via SARAH domain) with isoform 1 of NEK2. Interacts with ESR1 only in the presence of STK3/MST2. Interacts with WTIP and AJUBA.TISSUE SPECIFICITY Ubiquitously expressed in adult tissues with highest expression in the pancreas, aorta and interventricular septum and lowest expression in skeletal muscle. Expression was higher in fetal than in the adult heart. Expressed in various cell lines.PTM Phosphorylated by STK3/MST2 and STK4/MST1. Phosphorylation is not required for SAV1 stability and may increase the number of protein binding sites on the scaffold molecule. UniProt Q9H4B6 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] Chain Coordinates 1 EQUAL 383 EQUAL Reactome Database ID Release 83 2028281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028281 Reactome R-HSA-2028281 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028281.1 Reactome DB_ID: 2028277 1 p-STK3 dimer [cytosol] p-STK3 dimer p-MST2 dimer Reactome DB_ID: 2028274 2 UniProt:Q13188 STK3 STK3 MST2 KRS1 STK3 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 NKX2-1 (By similarity). Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.ACTIVITY REGULATION Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-180, which are inhibited by the proto-oncogene product RAF1. Activated by RASSF1 which acts by preventing its dephosphorylation.SUBUNIT Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation (By similarity). Interacts with and stabilizes SAV1 (PubMed:15688006, PubMed:16930133, PubMed:28087714). Interacts with RAF1, which prevents dimerization and phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain) with isoform 1 of NEK2. Interacts with ESR1 only in the presence of SAV1. Interacts with PKB/AKT1. Forms a tripartite complex with MOBKL1B and STK38. Interacts with RASSF2 (via SARAH domain). Interacts with DLG5 (via PDZ domain 3) (PubMed:28087714). Interacts with LATS1; this interaction is inhibited in the presence of DLG5 (PubMed:28087714). Interacts with MARK3 in the presence of DLG5 (PubMed:28087714).TISSUE SPECIFICITY Expressed at high levels in adult kidney, skeletal and placenta tissues and at very low levels in adult heart, lung and brain tissues.INDUCTION Activity increases during mitosis.PTM Phosphorylation at Thr-117 and Thr-384 by PKB/AKT1, leads to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation, and increase in its binding to RAF1.PTM Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N).SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. UniProt Q13188 O-phospho-L-threonine at 180 180 EQUAL O-phospho-L-threonine [MOD:00047] 1 EQUAL 491 EQUAL Reactome Database ID Release 83 2028277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028277 Reactome R-HSA-2028277 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028277.1 Reactome Database ID Release 83 2028261 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028261 Reactome R-HSA-2028261 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028261.1 GO 0004674 GO molecular function Reactome Database ID Release 83 2028573 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028573 Reactome Database ID Release 83 2028635 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028635 Reactome R-HSA-2028635 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028635.2 18328708 Pubmed 2008 MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation Praskova, M Xia, F Avruch, Joseph Curr Biol 18:311-21