Signaling by Hippo (Homo sapiens)

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4, 5, 9-11, 14...7, 123, 8, 1726114191, 3, 17212, 15, 2825414, 161427101914, 1614251014, 161111, 18257, 21, 2615, 261466cytosolnucleoplasmp-SAV1 p-S89-WWTR1 ADPp-YAP1:YWHABATPAMOTL2 CASP3(176-277) p-SAV1 AMOT proteinsp-T12,T35-MOB1B TJP2ADPAMOT-1 p-STK3/N:p-SAV1MOB1WWTR1 CASP3(29-175) CASP3(176-277) p-T12,T35-MOB1A DVL2 YWHAE AMOTL1 p-S909,T1097-LATS1 YAP1:TJP2NPHP4YAP1:TJP2p-MOB1ATPp-T183-STK4(1-326) WWTR1 p-T180-STK3(1-491) YAP1- and WWTR1(TAZ)-stimulatedgene expressionp-5S-YAP1 YAP1KIBRA:LATSSTK3:SAV1AMOTL2 LATSATPAMOT:WWTR1 (TAZ)WWTR1:TJP2YAP1 LATS1 p-SAV1 Caspase-3ADPYAP1 p-LATS2:p-MOB1p-T180-STK3(1-322) p-T12,T35-MOB1B ATPp-STK4/N:p-SAV1p-T12,T35-MOB1B p-WWTR1:DVL2p-LATS:p-MOBp-T12,T35-MOB1A LATS1 LATS2 YWHAE ADPLATS2 ADPp-S89-WWTR1TJP1TJP2 DVL2WWC1p-YAP1p-S127-YAP1 WWTR1YWHAE dimerYWHAB p-LATS1:p-MOB1p-T12,T35-MOB1A p-T12,T35-MOB1B ATPp-T12,T35-MOB1B p-5S-YAP1 STK3(1-491) NPHP4:LATSp-S871,T1041-LATS2 AMOTL2 WWTR1 LATS1 YWHAB LATS1 LATS:p-MOBTJP2 p-5S-YAP1p-T183-STK4(1-487) AMOT-1 WWTR1:TJP1p-S127-YAP1 LATS2 YWHAB dimerTJP1 p-STK4:p-SAV1MOB1A Caspase-3p-S871,T1041-LATS2 ATPSTK4(327-487)p-T12,T35-MOB1A p-STK3:p-SAV1STK4(1-487) NPHP4 STK3(323-491)p-S89-WWTR1 WWC1 AMOT-1 p-SAV1 YAP1p-T12,T35-MOB1A LATS2 ADPAMOT:YAP1AMOTL1 ATPADPSAV1 MOB1B YAP1 STK4:SAV1p-WWTR1:YWHAECASP3(29-175) p-S127-YAP1p-S909,T1097-LATS1 AMOTL1 TJP2 WWTR1SAV1 11249, 222414, 1612624172712119106441225211, 1812514, 162626251471425131221246261, 171025


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). View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 2028269
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  1. Chan EH, Nousiainen M, Chalamalasetty RB, Schäfer A, Nigg EA, Silljé HH.; ''The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.''; PubMed Europe PMC
  2. 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
  3. Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J.; ''Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras.''; PubMed Europe PMC
  4. 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
  5. Sudol M, Harvey KF.; ''Modularity in the Hippo signaling pathway.''; PubMed Europe PMC
  6. Hao Y, Chun A, Cheung K, Rashidi B, Yang X.; ''Tumor suppressor LATS1 is a negative regulator of oncogene YAP.''; PubMed Europe PMC
  7. Yang X, Lee WH, Sobott F, Papagrigoriou E, Robinson CV, Grossmann JG, Sundström M, Doyle DA, Elkins JM.; ''Structural basis for protein-protein interactions in the 14-3-3 protein family.''; PubMed Europe PMC
  8. Creasy CL, Ambrose DM, Chernoff J.; ''The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain.''; PubMed Europe PMC
  9. Oh H, Irvine KD.; ''Yorkie: the final destination of Hippo signaling.''; PubMed Europe PMC
  10. 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
  11. 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
  12. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL.; ''Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.''; PubMed Europe PMC
  13. Chow A, Hao Y, Yang X.; ''Molecular characterization of human homologs of yeast MOB1.''; PubMed Europe PMC
  14. 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
  15. 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
  16. Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, Chernoff J, Clark EA, Krebs EG.; ''Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1.''; PubMed Europe PMC
  17. 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
  18. Wang W, Huang J, Chen J.; ''Angiomotin-like proteins associate with and negatively regulate YAP1.''; PubMed Europe PMC
  19. Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA, Sakuma R, Pawson T, Hunziker W, McNeill H, Wrana JL, Attisano L.; ''The Hippo pathway regulates Wnt/beta-catenin signaling.''; PubMed Europe PMC
  20. Zhao B, Li L, Lei Q, Guan KL.; ''The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version.''; PubMed Europe PMC
  21. Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB.; ''TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins.''; PubMed Europe PMC
  22. Murakami M, Nakagawa M, Olson EN, Nakagawa O.; ''A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.''; PubMed Europe PMC
  23. Pan D.; ''The hippo signaling pathway in development and cancer.''; PubMed Europe PMC
  24. Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMed Europe PMC
  25. Praskova M, Xia F, Avruch J.; ''MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation.''; PubMed Europe PMC
  26. Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL.; ''TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway.''; PubMed Europe PMC
  27. Xiao L, Chen Y, Ji M, Dong J.; ''KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.''; PubMed Europe PMC
  28. Paramasivam M, Sarkeshik A, Yates JR, Fernandes MJ, McCollum D.; ''Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
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

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AMOT proteinsComplexR-HSA-2028605 (Reactome)
AMOT-1 ProteinQ4VCS5-1 (Uniprot-TrEMBL)
AMOT:WWTR1 (TAZ)ComplexR-HSA-2028723 (Reactome)
AMOT:YAP1ComplexR-HSA-2028720 (Reactome)
AMOTL1 ProteinQ8IY63 (Uniprot-TrEMBL)
AMOTL2 ProteinQ9Y2J4 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CASP3(176-277) ProteinP42574 (Uniprot-TrEMBL)
CASP3(29-175) ProteinP42574 (Uniprot-TrEMBL)
Caspase-3ComplexR-HSA-350870 (Reactome)
DVL2 ProteinO14641 (Uniprot-TrEMBL)
DVL2ProteinO14641 (Uniprot-TrEMBL)
KIBRA:LATSComplexR-HSA-2038402 (Reactome)
LATS1 ProteinO95835 (Uniprot-TrEMBL)
LATS2 ProteinQ9NRM7 (Uniprot-TrEMBL)
LATS:p-MOBComplexR-HSA-2028543 (Reactome)
LATSComplexR-HSA-2028571 (Reactome)
MOB1A ProteinQ9H8S9 (Uniprot-TrEMBL)
MOB1B ProteinQ7L9L4 (Uniprot-TrEMBL)
MOB1ComplexR-HSA-2028544 (Reactome)
NPHP4 ProteinO75161 (Uniprot-TrEMBL)
NPHP4:LATSComplexR-HSA-2059920 (Reactome)
NPHP4ProteinO75161 (Uniprot-TrEMBL)
SAV1 ProteinQ9H4B6 (Uniprot-TrEMBL)
STK3(1-491) ProteinQ13188 (Uniprot-TrEMBL)
STK3(323-491)ProteinQ13188 (Uniprot-TrEMBL)
STK3:SAV1ComplexR-HSA-2028275 (Reactome)
STK4(1-487) ProteinQ13043 (Uniprot-TrEMBL)
STK4(327-487)ProteinQ13043 (Uniprot-TrEMBL)
STK4:SAV1ComplexR-HSA-2028286 (Reactome)
TJP1 ProteinQ07157 (Uniprot-TrEMBL)
TJP1ProteinQ07157 (Uniprot-TrEMBL)
TJP2 ProteinQ9UDY2 (Uniprot-TrEMBL)
TJP2ProteinQ9UDY2 (Uniprot-TrEMBL)
WWC1 ProteinQ8IX03 (Uniprot-TrEMBL)
WWC1ProteinQ8IX03 (Uniprot-TrEMBL)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
WWTR1:TJP1ComplexR-HSA-2064404 (Reactome)
WWTR1:TJP2ComplexR-HSA-2064405 (Reactome)
WWTR1ProteinQ9GZV5 (Uniprot-TrEMBL)
YAP1 ProteinP46937 (Uniprot-TrEMBL)
YAP1- and WWTR1

(TAZ)-stimulated

gene expression
PathwayR-HSA-2032785 (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).
YAP1:TJP2ComplexR-HSA-2064400 (Reactome)
YAP1:TJP2ComplexR-HSA-2064401 (Reactome)
YAP1ProteinP46937 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAB dimerComplexR-HSA-2028645 (Reactome)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAE dimerComplexR-HSA-194364 (Reactome)
p-5S-YAP1 ProteinP46937 (Uniprot-TrEMBL)
p-5S-YAP1ProteinP46937 (Uniprot-TrEMBL)
p-LATS1:p-MOB1ComplexR-HSA-2028559 (Reactome)
p-LATS2:p-MOB1ComplexR-HSA-2028584 (Reactome)
p-LATS:p-MOBComplexR-HSA-2028550 (Reactome)
p-MOB1ComplexR-HSA-2028620 (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/N:p-SAV1ComplexR-HSA-2028690 (Reactome)
p-STK3:p-SAV1ComplexR-HSA-2028261 (Reactome)
p-STK4/N:p-SAV1ComplexR-HSA-2028698 (Reactome)
p-STK4:p-SAV1ComplexR-HSA-2028266 (Reactome)
p-T12,T35-MOB1A ProteinQ9H8S9 (Uniprot-TrEMBL)
p-T12,T35-MOB1B ProteinQ7L9L4 (Uniprot-TrEMBL)
p-T180-STK3(1-322) ProteinQ13188 (Uniprot-TrEMBL)
p-T180-STK3(1-491) ProteinQ13188 (Uniprot-TrEMBL)
p-T183-STK4(1-326) ProteinQ13043 (Uniprot-TrEMBL)
p-T183-STK4(1-487) ProteinQ13043 (Uniprot-TrEMBL)
p-WWTR1:DVL2ComplexR-HSA-2066300 (Reactome)
p-WWTR1:YWHAEComplexR-HSA-2028649 (Reactome)
p-YAP1:YWHABComplexR-HSA-2028630 (Reactome)
p-YAP1ComplexR-HSA-2028622 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-2028284 (Reactome)
ADPArrowR-HSA-2028555 (Reactome)
ADPArrowR-HSA-2028583 (Reactome)
ADPArrowR-HSA-2028589 (Reactome)
ADPArrowR-HSA-2028591 (Reactome)
ADPArrowR-HSA-2028598 (Reactome)
ADPArrowR-HSA-2028629 (Reactome)
ADPArrowR-HSA-2028635 (Reactome)
ADPArrowR-HSA-2028661 (Reactome)
ADPArrowR-HSA-2028670 (Reactome)
ADPArrowR-HSA-2028673 (Reactome)
ADPArrowR-HSA-2028675 (Reactome)
ADPArrowR-HSA-2028679 (Reactome)
ADPArrowR-HSA-2060328 (Reactome)
AMOT proteinsArrowR-HSA-2028583 (Reactome)
AMOT proteinsArrowR-HSA-2028661 (Reactome)
AMOT proteinsR-HSA-2028724 (Reactome)
AMOT proteinsR-HSA-2028735 (Reactome)
AMOT:WWTR1 (TAZ)ArrowR-HSA-2028735 (Reactome)
AMOT:YAP1ArrowR-HSA-2028724 (Reactome)
ATPR-HSA-2028284 (Reactome)
ATPR-HSA-2028555 (Reactome)
ATPR-HSA-2028583 (Reactome)
ATPR-HSA-2028589 (Reactome)
ATPR-HSA-2028591 (Reactome)
ATPR-HSA-2028598 (Reactome)
ATPR-HSA-2028629 (Reactome)
ATPR-HSA-2028635 (Reactome)
ATPR-HSA-2028661 (Reactome)
ATPR-HSA-2028670 (Reactome)
ATPR-HSA-2028673 (Reactome)
ATPR-HSA-2028675 (Reactome)
ATPR-HSA-2028679 (Reactome)
ATPR-HSA-2060328 (Reactome)
Caspase-3mim-catalysisR-HSA-2028692 (Reactome)
Caspase-3mim-catalysisR-HSA-2028697 (Reactome)
DVL2R-HSA-2066299 (Reactome)
KIBRA:LATSArrowR-HSA-2038398 (Reactome)
LATS:p-MOBArrowR-HSA-2028626 (Reactome)
LATS:p-MOBR-HSA-2028555 (Reactome)
LATS:p-MOBR-HSA-2028589 (Reactome)
LATS:p-MOBR-HSA-2028673 (Reactome)
LATS:p-MOBR-HSA-2028679 (Reactome)
LATSR-HSA-2028626 (Reactome)
LATSR-HSA-2038398 (Reactome)
LATSR-HSA-2059926 (Reactome)
MOB1R-HSA-2028629 (Reactome)
MOB1R-HSA-2028635 (Reactome)
MOB1R-HSA-2028670 (Reactome)
MOB1R-HSA-2028675 (Reactome)
NPHP4:LATSArrowR-HSA-2059926 (Reactome)
NPHP4R-HSA-2059926 (Reactome)
R-HSA-2028284 (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).
R-HSA-2028555 (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).
R-HSA-2028583 (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).
R-HSA-2028589 (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).
R-HSA-2028591 (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).
R-HSA-2028598 (Reactome) Cytosolic phospho-LATS1, complexed with MOB1, catalyzes the phosphorylation of YAP on five serine residues (Hao et al. 2008).
R-HSA-2028626 (Reactome) Phosphoylated MOB1A proteins are able to associate with LATS proteins (Praskova et al. 2008).
R-HSA-2028629 (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).
R-HSA-2028635 (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).
R-HSA-2028644 (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).
R-HSA-2028651 (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).
R-HSA-2028661 (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).
R-HSA-2028670 (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.
R-HSA-2028673 (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.
R-HSA-2028675 (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.
R-HSA-2028679 (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.
R-HSA-2028692 (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).
R-HSA-2028697 (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).
R-HSA-2028724 (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).
R-HSA-2028735 (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).
R-HSA-2032768 (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).
R-HSA-2032770 (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).
R-HSA-2038398 (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).
R-HSA-2059926 (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).
R-HSA-2060328 (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).
R-HSA-2064406 (Reactome) The YAP1:ZO-2 (TJP2) complex can translocate to the nucleus (Oka et al. 2010).
R-HSA-2064417 (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.
R-HSA-2064418 (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.
R-HSA-2064421 (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.
R-HSA-2066299 (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.
STK3(323-491)ArrowR-HSA-2028697 (Reactome)
STK3:SAV1R-HSA-2028591 (Reactome)
STK3:SAV1mim-catalysisR-HSA-2028591 (Reactome)
STK4(327-487)ArrowR-HSA-2028692 (Reactome)
STK4:SAV1R-HSA-2028284 (Reactome)
STK4:SAV1mim-catalysisR-HSA-2028284 (Reactome)
TJP1R-HSA-2064417 (Reactome)
TJP2R-HSA-2064418 (Reactome)
TJP2R-HSA-2064421 (Reactome)
WWC1R-HSA-2038398 (Reactome)
WWTR1:TJP1ArrowR-HSA-2064417 (Reactome)
WWTR1:TJP2ArrowR-HSA-2064418 (Reactome)
WWTR1ArrowR-HSA-2032768 (Reactome)
WWTR1R-HSA-2028661 (Reactome)
WWTR1R-HSA-2028735 (Reactome)
WWTR1R-HSA-2032768 (Reactome)
WWTR1R-HSA-2060328 (Reactome)
WWTR1R-HSA-2064417 (Reactome)
WWTR1R-HSA-2064418 (Reactome)
YAP1:TJP2ArrowR-HSA-2064406 (Reactome)
YAP1:TJP2ArrowR-HSA-2064421 (Reactome)
YAP1:TJP2R-HSA-2064406 (Reactome)
YAP1ArrowR-HSA-2032770 (Reactome)
YAP1R-HSA-2028583 (Reactome)
YAP1R-HSA-2028598 (Reactome)
YAP1R-HSA-2028724 (Reactome)
YAP1R-HSA-2032770 (Reactome)
YAP1R-HSA-2064421 (Reactome)
YWHAB dimerR-HSA-2028644 (Reactome)
YWHAE dimerR-HSA-2028651 (Reactome)
p-5S-YAP1ArrowR-HSA-2028598 (Reactome)
p-LATS1:p-MOB1mim-catalysisR-HSA-2028598 (Reactome)
p-LATS1:p-MOB1mim-catalysisR-HSA-2060328 (Reactome)
p-LATS2:p-MOB1mim-catalysisR-HSA-2028583 (Reactome)
p-LATS2:p-MOB1mim-catalysisR-HSA-2028661 (Reactome)
p-LATS:p-MOBArrowR-HSA-2028555 (Reactome)
p-LATS:p-MOBArrowR-HSA-2028589 (Reactome)
p-LATS:p-MOBArrowR-HSA-2028673 (Reactome)
p-LATS:p-MOBArrowR-HSA-2028679 (Reactome)
p-MOB1ArrowR-HSA-2028629 (Reactome)
p-MOB1ArrowR-HSA-2028635 (Reactome)
p-MOB1ArrowR-HSA-2028670 (Reactome)
p-MOB1ArrowR-HSA-2028675 (Reactome)
p-MOB1R-HSA-2028626 (Reactome)
p-S127-YAP1ArrowR-HSA-2028583 (Reactome)
p-S89-WWTR1ArrowR-HSA-2028661 (Reactome)
p-S89-WWTR1ArrowR-HSA-2060328 (Reactome)
p-S89-WWTR1R-HSA-2028651 (Reactome)
p-S89-WWTR1R-HSA-2066299 (Reactome)
p-STK3/N:p-SAV1ArrowR-HSA-2028697 (Reactome)
p-STK3/N:p-SAV1mim-catalysisR-HSA-2028673 (Reactome)
p-STK3/N:p-SAV1mim-catalysisR-HSA-2028675 (Reactome)
p-STK3:p-SAV1ArrowR-HSA-2028591 (Reactome)
p-STK3:p-SAV1R-HSA-2028697 (Reactome)
p-STK3:p-SAV1mim-catalysisR-HSA-2028589 (Reactome)
p-STK3:p-SAV1mim-catalysisR-HSA-2028635 (Reactome)
p-STK4/N:p-SAV1ArrowR-HSA-2028692 (Reactome)
p-STK4/N:p-SAV1mim-catalysisR-HSA-2028670 (Reactome)
p-STK4/N:p-SAV1mim-catalysisR-HSA-2028679 (Reactome)
p-STK4:p-SAV1ArrowR-HSA-2028284 (Reactome)
p-STK4:p-SAV1R-HSA-2028692 (Reactome)
p-STK4:p-SAV1mim-catalysisR-HSA-2028555 (Reactome)
p-STK4:p-SAV1mim-catalysisR-HSA-2028629 (Reactome)
p-WWTR1:DVL2ArrowR-HSA-2066299 (Reactome)
p-WWTR1:YWHAEArrowR-HSA-2028651 (Reactome)
p-YAP1:YWHABArrowR-HSA-2028644 (Reactome)
p-YAP1R-HSA-2028644 (Reactome)

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