Signaling by Hippo (Homo sapiens)

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3-5, 8, 12...83, 235, 267, 9, 2010, 1836, 11, 1812212104152, 10, 1681191722557, 9, 1917195, 262, 655, 2641STK3SAV1 active caspase-3 STK4SAV1 SAV1 dimer LATS p-MOB1 YWHAE dimer AMOT proteins p-LATS YAP1TJP2 p-LATS2p-MOB1 STK4 dimer WWTR1TJP1 p-STK3 dimer p-LATS1p-MOB1 nucleoplasmp-STK3/N dimer p-MOB1 AMOT proteins p-STK3p-SAV1 SAV1 dimer WWTR1TJP2 YWHAE dimer p-STK4 dimer p-YAP1YWHAB p-SAV1 dimer p-STK4/N dimer YWHAB dimer p-SAV1 dimer KIBRALATS cytosolNPHP4LATS LATS LATSp-MOB AMOTWWTR1 p-STK4/Np-SAV1 p-MOB1 p-MOB1 p-WWTR1YWHAE p-STK4p-SAV1 p-YAP1 p-SAV1 dimer YAP1TJP2 active caspase-3 LATS YWHAB dimer AMOTYAP1 STK3 dimer p-SAV1 dimer p-WWTR1DVL2 p-STK3/Np-SAV1 p-LATSp-MOB p-T12,T35-MOB1Bp-S89-WWTR1 AMOT-1 YAP1 p-SAV1 AMOTL2 AMOTYAP1WWTR1TJP1p-5S-YAP1 p-5S-YAP1LATS2 ATPATPMOB1p-T12,T35-MOB1A ATPADPADPp-STK3p-SAV1YWHAB dimerAMOTWWTR1 p-S909,T1097-LATS1 ATPCASP3ADPp-T12,T35-MOB1A NPHP4LATSp-S127-YAP1 p-LATS2p-MOB1active caspase-3AMOT proteinsCASP3YWHABp-S871,T1041-LATS2 TJP2 p-WWTR1YWHAEp-SAV1 AMOTL1 YWHAE dimerADPp-S871,T1041-LATS2 STK3p-S909,T1097-LATS1 p-YAP1YWHABWWTR1 LATS1 AMOTL2 WWTR1p-WWTR1DVL2YAP1DVL2WWC1 p-T183-STK4DVL2p-STK4/Np-SAV1YWHABAMOT-1 WWTR1 WWTR1TJP2LATS2 ADPp-STK3/Np-SAV1CASP3p-T12,T35-MOB1BADPp-LATS1p-MOB1p-T12,T35-MOB1A p-MOB1STK4LATS2 p-S89-WWTR1 p-T180-STK3KIBRALATSATPYWHAE CASP3p-T183-STK4YAP1TJP2p-T180-STK3STK3SAV1p-STK4p-SAV1STK3ATPp-YAP1TJP1TJP2 NPHP4p-T12,T35-MOB1A LATS1 p-SAV1 LATSp-MOBYAP1- and WWTR1 TJP2 ADPNPHP4 YAP1 p-T12,T35-MOB1Bp-S127-YAP1WWC1ATPSTK4YAP1 STK4SAV1YAP1TJP2SAV1 p-LATSp-MOBYWHAE WWTR1 WWTR1LATS1 LATSSAV1 TJP2TJP1 p-T12,T35-MOB1BAMOTL1 YAP1p-SAV1 active caspase-3p-S89-WWTR121, 251199, 1913274272218191722745125, 2659156271327163, 231766101022110275, 26


Description

Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010; Pan 2010; Zhao et al. 2010). This group of reactions is also notable for its abundance of protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).

There are two human homologues of each of the three Drosophila kinases, whose functions are well conserved: expression of human proteins rescues fly mutants. The two members of each pair of human homologues have biochemically indistinguishable functions. Autophosphorylated STK3 (MST2) and STK4 (MST1) (homologues of Drosophila Hippo) catalyze the phosphorylation and activation of LATS1 and LATS2 (homologues of Drosophila Warts) and of the accessory proteins MOB1A and MOB1B (homologues of Drosophila Mats). LATS1 and LATS2 in turn catalyze the phosphorylation of the transcriptional co-activators YAP1 and WWTR1 (TAZ) (homologues of Drosophila Yorkie).<p>In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.<p>Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).<p>In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade. A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.<p>Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010; Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=2028269</div>

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Bibliography

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  10. Callus BA, Verhagen AM, Vaux DL.; ''Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.''; PubMed Europe PMC Scholia
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  14. Chan SW, Lim CJ, Chong YF, Pobbati AV, Huang C, Hong W.; ''Hippo pathway-independent restriction of TAZ and YAP by angiomotin.''; PubMed Europe PMC Scholia
  15. Oka T, Remue E, Meerschaert K, Vanloo B, Boucherie C, Gfeller D, Bader GD, Sidhu SS, Vandekerckhove J, Gettemans J, Sudol M.; ''Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling.''; PubMed Europe PMC Scholia
  16. Habbig S, Bartram MP, Müller RU, Schwarz R, Andriopoulos N, Chen S, Sägmüller JG, Hoehne M, Burst V, Liebau MC, Reinhardt HC, Benzing T, Schermer B.; ''NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.''; PubMed Europe PMC Scholia
  17. Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S.; ''MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation.''; PubMed Europe PMC Scholia
  18. Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, Guan KL.; ''Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.''; PubMed Europe PMC Scholia
  19. Remue E, Meerschaert K, Oka T, Boucherie C, Vandekerckhove J, Sudol M, Gettemans J.; ''TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner.''; PubMed Europe PMC Scholia
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  24. Sudol M, Harvey KF.; ''Modularity in the Hippo signaling pathway.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115016view16:55, 25 January 2021ReactomeTeamReactome version 75
113461view11:53, 2 November 2020ReactomeTeamReactome version 74
112661view16:04, 9 October 2020ReactomeTeamReactome version 73
101577view11:44, 1 November 2018ReactomeTeamreactome version 66
101113view21:28, 31 October 2018ReactomeTeamreactome version 65
100641view20:02, 31 October 2018ReactomeTeamreactome version 64
100191view16:47, 31 October 2018ReactomeTeamreactome version 63
99741view15:13, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99307view12:46, 31 October 2018ReactomeTeamreactome version 62
93955view13:47, 16 August 2017ReactomeTeamreactome version 61
93551view11:26, 9 August 2017ReactomeTeamreactome version 61
87174view19:51, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86653view09:23, 11 July 2016ReactomeTeamreactome version 56
83116view10:01, 18 November 2015ReactomeTeamVersion54
81456view12:59, 21 August 2015ReactomeTeamVersion53
76930view08:20, 17 July 2014ReactomeTeamFixed remaining interactions
76635view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
75965view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75668view10:58, 10 June 2014ReactomeTeamReactome 48 Update
75023view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74667view08:43, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AMOT WWTR1 ComplexREACT_120141 (Reactome)
AMOT YAP1ComplexREACT_119692 (Reactome)
AMOT proteinsProteinREACT_119439 (Reactome)
AMOT-1 ProteinQ4VCS5-1 (Uniprot-TrEMBL)
AMOTL1 ProteinQ8IY63 (Uniprot-TrEMBL)
AMOTL2 ProteinQ9Y2J4 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CASP3ProteinP42574 (Uniprot-TrEMBL)
DVL2ProteinO14641 (Uniprot-TrEMBL)
KIBRA LATSComplexREACT_119048 (Reactome)
LATS p-MOBComplexREACT_119861 (Reactome)
LATS1 ProteinO95835 (Uniprot-TrEMBL)
LATS2 ProteinQ9NRM7 (Uniprot-TrEMBL)
LATSProteinREACT_118962 (Reactome)
MOB1ProteinREACT_118992 (Reactome)
NPHP4 LATSComplexREACT_119950 (Reactome)
NPHP4 ProteinO75161 (Uniprot-TrEMBL)
NPHP4ProteinO75161 (Uniprot-TrEMBL)
SAV1 ProteinQ9H4B6 (Uniprot-TrEMBL)
STK3 SAV1ComplexREACT_118889 (Reactome)
STK3ProteinQ13188 (Uniprot-TrEMBL)
STK4 SAV1ComplexREACT_119056 (Reactome)
STK4ProteinQ13043 (Uniprot-TrEMBL)
TJP1 ProteinQ07157 (Uniprot-TrEMBL)
TJP1ProteinQ07157 (Uniprot-TrEMBL)
TJP2 ProteinQ9UDY2 (Uniprot-TrEMBL)
TJP2ProteinQ9UDY2 (Uniprot-TrEMBL)
WWC1 ProteinQ8IX03 (Uniprot-TrEMBL)
WWC1ProteinQ8IX03 (Uniprot-TrEMBL)
WWTR1 TJP1ComplexREACT_119540 (Reactome)
WWTR1 TJP2ComplexREACT_119772 (Reactome)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
YAP1 TJP2ComplexREACT_118921 (Reactome)
YAP1 TJP2ComplexREACT_119487 (Reactome)
YAP1 ProteinP46937 (Uniprot-TrEMBL)
YAP1- and WWTR1 PathwayREACT_118713 (Reactome) YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010).
YAP1ProteinP46937 (Uniprot-TrEMBL)
YWHAB dimerComplexREACT_120053 (Reactome)
YWHABProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAE dimerComplexREACT_14118 (Reactome)
active caspase-3ComplexREACT_2467 (Reactome)
p-5S-YAP1 ProteinP46937 (Uniprot-TrEMBL)
p-5S-YAP1ProteinP46937 (Uniprot-TrEMBL)
p-LATS p-MOBComplexREACT_118982 (Reactome)
p-LATS1 p-MOB1ComplexREACT_119829 (Reactome)
p-LATS2 p-MOB1ComplexREACT_120047 (Reactome)
p-MOB1ProteinREACT_119145 (Reactome)
p-S127-YAP1 ProteinP46937 (Uniprot-TrEMBL)
p-S127-YAP1ProteinP46937 (Uniprot-TrEMBL)
p-S871,T1041-LATS2 ProteinQ9NRM7 (Uniprot-TrEMBL)
p-S89-WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
p-S89-WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
p-S909,T1097-LATS1 ProteinO95835 (Uniprot-TrEMBL)
p-SAV1 ProteinQ9H4B6 (Uniprot-TrEMBL)
p-STK3 p-SAV1ComplexREACT_119188 (Reactome)
p-STK3/N p-SAV1ComplexREACT_119801 (Reactome)
p-STK4 p-SAV1ComplexREACT_120086 (Reactome)
p-STK4/N p-SAV1ComplexREACT_120272 (Reactome)
p-T12,T35-MOB1A ProteinQ9H8S9 (Uniprot-TrEMBL)
p-T12,T35-MOB1BProteinQ7L9L4 (Uniprot-TrEMBL)
p-T180-STK3ProteinQ13188 (Uniprot-TrEMBL)
p-T183-STK4ProteinQ13043 (Uniprot-TrEMBL)
p-WWTR1 DVL2ComplexREACT_120163 (Reactome)
p-WWTR1 YWHAEComplexREACT_119876 (Reactome)
p-YAP1 YWHABComplexREACT_119234 (Reactome)
p-YAP1ProteinREACT_119346 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowREACT_118559 (Reactome)
ADPArrowREACT_118609 (Reactome)
ADPArrowREACT_118615 (Reactome)
ADPArrowREACT_118649 (Reactome)
ADPArrowREACT_118652 (Reactome)
ADPArrowREACT_118669 (Reactome)
ADPArrowREACT_118698 (Reactome)
ADPArrowREACT_118702 (Reactome)
ADPArrowREACT_118711 (Reactome)
ADPArrowREACT_118768 (Reactome)
ADPArrowREACT_118786 (Reactome)
ADPArrowREACT_118829 (Reactome)
ADPArrowREACT_118842 (Reactome)
ADPArrowREACT_118858 (Reactome)
AMOT proteinsArrowREACT_118702 (Reactome)
AMOT proteinsArrowREACT_118829 (Reactome)
AMOT proteinsREACT_118701 (Reactome)
AMOT proteinsREACT_118821 (Reactome)
ATPREACT_118559 (Reactome)
ATPREACT_118609 (Reactome)
ATPREACT_118615 (Reactome)
ATPREACT_118649 (Reactome)
ATPREACT_118652 (Reactome)
ATPREACT_118669 (Reactome)
ATPREACT_118698 (Reactome)
ATPREACT_118702 (Reactome)
ATPREACT_118711 (Reactome)
ATPREACT_118768 (Reactome)
ATPREACT_118786 (Reactome)
ATPREACT_118829 (Reactome)
ATPREACT_118842 (Reactome)
ATPREACT_118858 (Reactome)
DVL2REACT_118667 (Reactome)
LATS p-MOBREACT_118609 (Reactome)
LATS p-MOBREACT_118669 (Reactome)
LATS p-MOBREACT_118786 (Reactome)
LATS p-MOBREACT_118858 (Reactome)
LATSREACT_118627 (Reactome)
LATSREACT_118831 (Reactome)
LATSREACT_118857 (Reactome)
MOB1REACT_118559 (Reactome)
MOB1REACT_118615 (Reactome)
MOB1REACT_118698 (Reactome)
MOB1REACT_118768 (Reactome)
NPHP4REACT_118831 (Reactome)
REACT_118559 (Reactome) Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK4(MST1)/N (Graves et al. 1998; Lee et al. 2001). 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.
REACT_118582 (Reactome) Cytosolic caspase 3 cleaves p-STK4 (p-MST1) to yield an active animo-terminal fragment (p-STK4/N) and a carboxy-terminal fragment (p-STK4/C) (Graves et al. 1998; Lee et al. 2001). The association of p-STK4 (p-MST1) with other proteins at the time of its cleavage by caspase has not been studied experimentally. Here, it is inferred to be dimerized and in a complex with SAV1 because that is the form of the molecule that becomes phosphorylated and phosphorylation appears normally to precede caspase cleavage. The effect of the cleavage is to increase the kinase activity of p-STK4 (p-MST1).
REACT_118592 (Reactome) In its unphosphorylated state, the YAP1 transcriptional coactivator moves freely into the nucleus. Phosphorylated YAP1, in contrast, is sequestered in the cytosol (Hao et al. 2008).
REACT_118609 (Reactome) Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK4(MST1)/N (Graves et al. 1998; Lee et al. 2001). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 (MST1) kinase. The target residues of LATS2 have not been identified experiemntally but are inferred to be serine-871 and threonine-1041 based on sequence similarity.
REACT_118615 (Reactome) Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK3(MST2)/N (Lee et al. 2001). 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.
REACT_118627 (Reactome) Phosphoylated MOB1A proteins are able to associate with LATS proteins (Praskova et al. 2008).
REACT_118640 (Reactome) Cytosolic caspase 3 cleaves p-STK3 (p-MST2) to yield an active animo-terminal fragment (p-STK3/N) and a carboxy-terminal fragment (p-STK3/C) (Lee et al. 2001). The association of p-STK3 (p-MST2) with other proteins at the time of its cleavage by caspase has not been studied experimentally. Here, it is inferred to be dimerized and in a complex with SAV1 because that is the form of the molecule that becomes phosphorylated and phosphorylation appears normally to precede caspase cleavage. The effect of the cleavage is to increase the kinase activity of p-STK3 (p-MST2).
REACT_118649 (Reactome) Cytosolic phospho-LATS1, complexed with MOB1, catalyzes the phosphorylation of WWTR1 (TAZ) on serine residue 89. This activity of human LATS1 protein has not been demonstrated experimentally but is inferred from the activity of human paralogue LATS2 and of mouse homologue LATS1 (Varelas et al. 2010).
REACT_118652 (Reactome) The serine/threonine kinase STK3 (MST2) catalyzes its own autophosphorylation as well as the phosphorylation of SAV1. These two reactions are annotated here as a single concerted process that takes place in a tetrameric complex containing two STK3 (MST2) subunits and two SAV1 subunits, based on the observations that STK3 (MST2) can catalyze both phosphorylation reactions in vitro, as well as the observations that each protein dimerizes and that STK3 (MST2) and SAV1 associate to form a complex. The order in which the various components associate, the stoichiometry of the complex ultimately formed, and the point(s) in this association process at which phosphoryltion occurs have not been established in vitro or in vivo, however (Callus et al. 2006; Praskova et al. 2004).
REACT_118667 (Reactome) Phosphorylated WWTR1 (TAZ) and DVL interact to form a complex in the cytosol. Thus sequestered, DVL2 is unable to undergo phosphorylation by casein kinase, inhibiting its role in WNT signaling. WWTR1 - DLV interaction thus appears to link the Hippo and WNT signaling processes (Varelas et al. 2010). The stoichiometry of the WWTR1:DVL complex is unknown.
REACT_118669 (Reactome) Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK3 (p-MST2). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Likewise, phosphorylated (active) STK3 (p-MST2) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 kinase (MST1); STK3 (MST2) is inferred to act similarly. The target residues of LATS2 have not been identified experimentally but are inferred to be serine-871 and threonine-1041 based on sequence similarity (Chan et al. 2005).
REACT_118676 (Reactome) In its unphosphorylated state, the WWTR1 (TAZ) transcriptional coactivator moves freely into the nucleus. Phosphorylated WWTR1 (TAZ), in contrast, is sequestered in the cytosol (Lei et al. 2008).
REACT_118698 (Reactome) 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).
REACT_118701 (Reactome) AMOT (130 KDa isoform), AMOTL1, and AMOTL2 can each bind YAP1 and sequester it in the cytosol. This interaction is not dependent on YAP1 phosphorylation and may thus be a means of negatively regulating YAP activity in addition to the ones dependent on Hippo pathway-dependent phosphorylation. AMOT - YAP1 binding is dependent on sequence motifs in the amino terminal portions of the AMOT proteins (and that are absent from the AMOT 80 KDa isoform, which does not bind YAP1) (Wang et al. 2010; Chan et al. 2011).
REACT_118702 (Reactome) Cytosolic phospho-LATS2, complexed with MOB1, catalyzes the phosphorylation of WWTR1 (TAZ) on serine residue 89 (Lei et al. 2008). This reaction is positively regulated by the angiomotin proteins AMOT (130 kd form), AMOTL1, and AMOTL2, which may function by physically bridging LATS2 and YAP (Zhao et al. 2011).
REACT_118711 (Reactome) Cytosolic phospho-LATS1, complexed with MOB1, catalyzes the phosphorylation of YAP on five serine residues (Hao et al. 2008).
REACT_118750 (Reactome) Cytosolic ZO-1 (TJP1) binds WWTR1 (TAZ) to form a complex. This event may play a role in sequestering WWTR1 in the cytosol (Remue et al. 2010). The phosphorylation state of the WWTR1 protein involved in this interaction has not been determined experimentally; it is inferred to be unphosphorylated.
REACT_118768 (Reactome) Cytosolic MOB1A and MOB1B are phosphorylated by phospho-STK4 (p-MST1). Phosphorylated (active) STK4 (p-MST1) 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).
REACT_118786 (Reactome) Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK4 (p-MST1). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Likewise, phosphorylated (active) STK4 (p-MST1) and SAV1 are known to form a complex and that complex is annotated as the catalyst of this reaction. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 (MST1) kinase. The target residues of LATS2 have not been identified experimentally but are inferred to be serine-871 and threonine-1041 based on sequence similarity (Chan et al. 2005).
REACT_118797 (Reactome) Cytosolic ZO-2 (TJP2) binds WWTR1 (TAZ) to form a complex. This event may play a role in sequestering WWTR1 in the cytosol (Remue et al. 2010). The phosphorylation state of the WWTR1 protein involved in this interaction has not been determined experimentally; it is inferred to be unphosphorylated.
REACT_118801 (Reactome) YWHAB (14-3-3 beta/alpha) binds phosphorylated YAP1 proteins, sequestering them in the cytosol. Structural studies indicate that the active form of YWHAB (14-3-3 beta/alpha) is a homodimer (Yang et al. 2006); the stoichiometry of its complex with YAP1 is unknown and has been annotated arbitrarily here to involve one YAP1 molecule and a YWHAB (14-3-3 beta/alpha) dimer. While YAP1 can be phosphorylated on several serine residues, phosphorylation of serine-127 appears to be critical for YWHAB(14-3-3 beta/alpha) binding (Zhao et al. 2007).
REACT_118821 (Reactome) AMOT (130 KDa isoform) and AMOTL1 can each bind WWTR1 (TAZ) and sequester it in the cytosol. AMOTL2 - WWTR1 binding has not been studied but is inferred to occur from the presence of key binding sequence motifs in AMOTL2 protein and from its known binding activity with YAP1, a WWTR1 homolog. These interactions are not dependent on WWTR1 phosphorylation and may thus be a means of negatively regulating WWTR1 activity in addition to the ones dependent on Hippo pathway-dependent phosphorylation. AMOT - WWTR1 binding is dependent on sequence motifs in the amino terminal portions of the AMOT proteins (and that are absent from the AMOT 80 KDa isoform) (Chan et al. 2011).
REACT_118822 (Reactome) The YAP1:ZO-2 (TJP2) complex can translocate to the nucleus (Oka et al. 2010).
REACT_118825 (Reactome) Cytosolic ZO-2 (TJP2) binds YAP1 to form a complex (Oka et al. 2010). The phosphorylation state of the YAP1 protein involved in this interaction has not been determined experimentally; it is inferred to be unphosphorylated.
REACT_118829 (Reactome) Cytosolic phospho-LATS2, complexed with MOB1, catalyzes the phosphorylation of YAP on serine residue 127 (and possibly other serine residues) (Zhao et al. 2007). This reaction is positively regulated by the angiomotin proteins AMOT (130 kd form), AMOTL1, and AMOTL2, which may function by physically bridging LATS2 and YAP (Paramasivam et al. 2011; Zhao et al. 2011).
REACT_118831 (Reactome) Cytosolic NPHP4 protein binds LATS proteins to form a complex. The stoiciometry of the resulting complex is unknown. When bound to NPHP4, LATS is unable to phosphorylate YAP1 and WWTR1 (TAZ) proteins, so the effect of NPHP4 binding is to antagonize this aspect of the Hippo cascade (Habbig et al. 2011).
REACT_118842 (Reactome) The serine/threonine kinase STK4 (MST1) catalyzes its own autophosphorylation as well as the phosphorylation of SAV1. These two reactions are annotated here as a single concerted process that takes place in a tetrameric complex containing two STK4 (MST1) subunits and two SAV1 subunits, based on the observations that STK4 (MST1) can catalyze both phosphorylation reactions in vitro, as well as the observations that each protein dimerizes and that STK4 (MST1) and SAV1 associate to form a complex. The order in which the various components associate, the stoichiometry of the complex ultimately formed, and the point(s) in this association process at which phosphoryltion occurs have not been established in vitro or in vivo, however (Callus et al. 2006; Creasy et al. 1996; Praskova et al. 2004).
REACT_118843 (Reactome) YWHAE (14-3-3 epsilon) binds phosphorylated WWTR1 (TAZ), sequestering it in the cytosol. Structural studies indicate that the active form of YWHAE (14-3-3 epsilon) is a homodimer (Yang et al. 2006); the stoichiometry of its complex with WWTR1 (TAZ) is unknown and has been annotated arbitrarily here to involve one WWTR1 (TAZ) molecule and a YWHAE(14-3-3 epsilon) dimer. Phosphorylation of serine residue 127 of WWTR1 (TAZ) appears to be critical for YWHAE (14-3-3 epsilon) binding (Kanai et al. 2000; Lei et al. 2008).
REACT_118857 (Reactome) Cytosolic KIBRA (WWC1) binds LATS proteins. The stoichiometry of the resulting complex is unlnown. The interaction of KIBRA with LATS directly or indirectly stimulates the phosphorylation of the latter proteins, so this interaction may promote LATS activation and, ultimately, YAP1 and TAZ sequestration in vivo (Xiao et al. 2011).
REACT_118858 (Reactome) Cytosolic LATS1 and LATS2 are phosphorylated by phospho-STK3 (MST2)/N (Lee et al. 2001). LATS proteins are known to form complexes with MOB1 proteins and this reaction is annotated with LATS:MOB1 complexes as its substrate. Serine-909 and threonine-1097 have been identified as LATS1 residues phosphorylated by STK4 (MST1) kinase; STK3(MST2)/N is inferred to act similarly. The target residues of LATS2 have not been identified experimentally but are inferred to be serine-871 and threonine-1041 based on sequence similarity.
STK3 SAV1REACT_118652 (Reactome)
STK3 SAV1mim-catalysisREACT_118652 (Reactome)
STK3ArrowREACT_118640 (Reactome)
STK4 SAV1REACT_118842 (Reactome)
STK4 SAV1mim-catalysisREACT_118842 (Reactome)
STK4ArrowREACT_118582 (Reactome)
TJP1REACT_118750 (Reactome)
TJP2REACT_118797 (Reactome)
TJP2REACT_118825 (Reactome)
WWC1REACT_118857 (Reactome)
WWTR1REACT_118649 (Reactome)
WWTR1REACT_118702 (Reactome)
WWTR1REACT_118750 (Reactome)
WWTR1REACT_118797 (Reactome)
WWTR1REACT_118821 (Reactome)
YAP1REACT_118701 (Reactome)
YAP1REACT_118711 (Reactome)
YAP1REACT_118825 (Reactome)
YAP1REACT_118829 (Reactome)
YWHAB dimerREACT_118801 (Reactome)
YWHAE dimerREACT_118843 (Reactome)
active caspase-3mim-catalysisREACT_118582 (Reactome)
active caspase-3mim-catalysisREACT_118640 (Reactome)
p-5S-YAP1ArrowREACT_118711 (Reactome)
p-LATS p-MOBArrowREACT_118609 (Reactome)
p-LATS p-MOBArrowREACT_118669 (Reactome)
p-LATS p-MOBArrowREACT_118786 (Reactome)
p-LATS p-MOBArrowREACT_118858 (Reactome)
p-LATS1 p-MOB1mim-catalysisREACT_118649 (Reactome)
p-LATS1 p-MOB1mim-catalysisREACT_118711 (Reactome)
p-LATS2 p-MOB1mim-catalysisREACT_118702 (Reactome)
p-LATS2 p-MOB1mim-catalysisREACT_118829 (Reactome)
p-MOB1ArrowREACT_118559 (Reactome)
p-MOB1ArrowREACT_118615 (Reactome)
p-MOB1ArrowREACT_118698 (Reactome)
p-MOB1ArrowREACT_118768 (Reactome)
p-MOB1REACT_118627 (Reactome)
p-S127-YAP1ArrowREACT_118829 (Reactome)
p-S89-WWTR1ArrowREACT_118649 (Reactome)
p-S89-WWTR1ArrowREACT_118702 (Reactome)
p-S89-WWTR1REACT_118667 (Reactome)
p-S89-WWTR1REACT_118843 (Reactome)
p-STK3 p-SAV1ArrowREACT_118652 (Reactome)
p-STK3 p-SAV1mim-catalysisREACT_118669 (Reactome)
p-STK3 p-SAV1mim-catalysisREACT_118698 (Reactome)
p-STK3/N p-SAV1ArrowREACT_118640 (Reactome)
p-STK3/N p-SAV1mim-catalysisREACT_118615 (Reactome)
p-STK3/N p-SAV1mim-catalysisREACT_118858 (Reactome)
p-STK4 p-SAV1ArrowREACT_118842 (Reactome)
p-STK4 p-SAV1mim-catalysisREACT_118768 (Reactome)
p-STK4 p-SAV1mim-catalysisREACT_118786 (Reactome)
p-STK4/N p-SAV1ArrowREACT_118582 (Reactome)
p-STK4/N p-SAV1mim-catalysisREACT_118559 (Reactome)
p-STK4/N p-SAV1mim-catalysisREACT_118609 (Reactome)
p-YAP1REACT_118801 (Reactome)

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