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• W3091176621 abstract "The Hippo pathway plays an important role in developmental biology, mediating organ size by controlling cell proliferation through the activity of a core kinase cassette. Multiple upstream events activate the pathway, but how each controls this core kinase cassette is not fully understood. Activation of the core kinase cassette begins with phosphorylation of the kinase MST1/2 (also known as STK3/4). Here, using a combination of in vitro biochemistry and cell-based assays, including chemically induced dimerization and single-molecule pulldown, we revealed that increasing the proximity of adjacent kinase domains, rather than formation of a specific protein assembly, is sufficient to trigger autophosphorylation. We validate this mechanism in cells and demonstrate that multiple events associated with the active pathway, including SARAH domain–mediated homodimerization, membrane recruitment, and complex formation with the effector protein SAV1, each increase the kinase domain proximity and autophosphorylation of MST2. Together, our results reveal that multiple and distinct upstream signals each utilize the same common molecular mechanism to stimulate MST2 autophosphorylation. This mechanism is likely conserved among MST2 homologs. Our work also highlights potential differences in Hippo signal propagation between each activating event owing to differences in the dynamics and regulation of each protein ensemble that triggers MST2 autophosphorylation and possible redundancy in activation. The Hippo pathway plays an important role in developmental biology, mediating organ size by controlling cell proliferation through the activity of a core kinase cassette. Multiple upstream events activate the pathway, but how each controls this core kinase cassette is not fully understood. Activation of the core kinase cassette begins with phosphorylation of the kinase MST1/2 (also known as STK3/4). Here, using a combination of in vitro biochemistry and cell-based assays, including chemically induced dimerization and single-molecule pulldown, we revealed that increasing the proximity of adjacent kinase domains, rather than formation of a specific protein assembly, is sufficient to trigger autophosphorylation. We validate this mechanism in cells and demonstrate that multiple events associated with the active pathway, including SARAH domain–mediated homodimerization, membrane recruitment, and complex formation with the effector protein SAV1, each increase the kinase domain proximity and autophosphorylation of MST2. Together, our results reveal that multiple and distinct upstream signals each utilize the same common molecular mechanism to stimulate MST2 autophosphorylation. This mechanism is likely conserved among MST2 homologs. Our work also highlights potential differences in Hippo signal propagation between each activating event owing to differences in the dynamics and regulation of each protein ensemble that triggers MST2 autophosphorylation and possible redundancy in activation. The Hippo pathway regulates a variety of biological processes, ranging from control of organ size during development to decisions of cell fate and the suppression of tumorigenesis (1Boggiano J.C. Fehon R.G. Growth control by committee: intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling.Dev. Cell. 2012; 22 (22516196): 695-70210.1016/j.devcel.2012.03.013Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 2Karaman R. Halder G. Cell junctions in Hippo signaling.Cold Spring Harbor Perspect. Biol. 2018; 10 (28600393): a02875310.1101/cshperspect.a028753Crossref PubMed Scopus (35) Google Scholar, 3Misra J.R. Irvine K.D. The Hippo signaling network and its biological functions.Annu. Rev. Genet. 2018; 52 (30183404): 65-8710.1146/annurev-genet-120417-031621Crossref PubMed Scopus (131) Google Scholar, 4Zheng Y. Pan D. The Hippo signaling pathway in development and disease.Dev. Cell. 2019; 50 (31386861): 264-28210.1016/j.devcel.2019.06.003Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 5Davis J.R. Tapon N. Hippo signalling during development.Development. 2019; 146 (31527062): dev16710610.1242/dev.167106Crossref PubMed Scopus (19) Google Scholar). In recent years, the Hippo pathway has emerged as a potential therapeutic target for the treatment of cancer and stimulation of tissue regeneration (6Moya I.M. Halder G. Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20 (30546055): 211-22610.1038/s41580-018-0086-yCrossref PubMed Scopus (199) Google Scholar, 7Dey A. Varelas X. Guan K.-L. Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine.Nat. Rev. Drug Discov. 2020; 19 (32555376): 480-49410.1038/s41573-020-0070-zCrossref PubMed Scopus (71) Google Scholar). The Hippo pathway is a growth control pathway that is conserved from mammals to flies; the names of individual proteins, however, are different. Mammalian genes can rescue the phenotypes of flies lacking homologous genes (8Wu S. Huang J. Dong J. Pan D. hippo Encodes a Ste-20 Family Protein Kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador warts.Cell. 2003; 114 (12941273): 445-45610.1016/S0092-8674(03)00549-XAbstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar, 9Lai Z.-C. Wei X. Shimizu T. Ramos E. Rohrbaugh M. Nikolaidis N. Ho L.-L. Li Y. Control of cell proliferation and apoptosis by Mob as tumor suppressor, Mats.Cell. 2005; 120 (15766530): 675-68510.1016/j.cell.2004.12.036Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 10Huang J. Wu S. Barrera J. Matthews K. Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP.Cell. 2005; 122 (16096061): 421-43410.1016/j.cell.2005.06.007Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar). The pathway was originally identified in Drosophila as a pathway that, when disrupted, leads to overgrowth phenotypes (8Wu S. Huang J. Dong J. Pan D. hippo Encodes a Ste-20 Family Protein Kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador warts.Cell. 2003; 114 (12941273): 445-45610.1016/S0092-8674(03)00549-XAbstract Full Text Full Text PDF PubMed Scopus (751) Google Scholar, 11Justice R.W. Zilian O. Woods D.F. Noll M. Bryant P.J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation.Genes Dev. 1995; 9 (7698644): 534-54610.1101/gad.9.5.534Crossref PubMed Scopus (671) Google Scholar, 12Xu T. Wang W. Zhang S. Stewart R.A. Yu W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.Development. 1995; 121 (7743921): 1053-1063Crossref PubMed Google Scholar, 13Tapon N. Harvey K.F. Bell D.W. Wahrer D.C.R. Schiripo T.A. Haber D.A. Hariharan I.K. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.Cell. 2002; 110 (12202036): 467-47810.1016/S0092-8674(02)00824-3Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 14Kango-Singh M. Nolo R. Tao C. Verstreken P. Hiesinger P.R. Bellen H.J. Halder G. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila.Development. 2002; 129 (12421711): 5719-573010.1242/dev.00168Crossref PubMed Scopus (255) Google Scholar, 15Harvey K.F. Pfleger C.M. Hariharan I.K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis.Cell. 2003; 114 (12941274): 457-46710.1016/S0092-8674(03)00557-9Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar, 16Udan, R. S., Kango-Singh, M., Nolo, R., Tao, C., and Halder, G., (2003) Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat. Cell Biol. 5, 914–920, 10.1038/ncb1050, 14502294.Google Scholar). The role of this pathway is conserved in mammals, as disruption of the pathway in mouse models leads to tumorigenesis (17Camargo F.D. Gokhale S. Johnnidis J.B. Fu D. Bell G.W. Jaenisch R. Brummelkamp T.R. YAP1 increases organ size and expands undifferentiated progenitor cells.Curr. Biol. 2007; 17 (17980593): 2054-206010.1016/j.cub.2007.10.039Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar, 18Dong J. Feldmann G. Huang J. Wu S. Zhang N. Comerford S.A. Gayyed M.F. Anders R.A. Maitra A. Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals.Cell. 2007; 130 (17889654): 1120-113310.1016/j.cell.2007.07.019Abstract Full Text Full Text PDF PubMed Scopus (1593) Google Scholar, 19Overholtzer M. Zhang J. Smolen G.A. Muir B. Li W. Sgroi D.C. Deng C.-X. Brugge J.S. Haber D.A. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.Proc. Natl. Acad. Sci. U. S. A. 2006; 103 (16894141): 12405-1241010.1073/pnas.0605579103Crossref PubMed Scopus (690) Google Scholar, 20McClatchey A.I. Giovannini M. Membrane organization and tumorigenesis–the NF2 tumor suppressor, Merlin.Genes Dev. 2005; 19 (16204178): 2265-227710.1101/gad.1335605Crossref PubMed Scopus (198) Google Scholar). In contrast to most canonical signaling pathways, the Hippo pathway is not activated by a single ligand:receptor pair. Instead, a variety of signals activate the pathway, including cell-cell contacts, the extracellular matrix, nutrients, stress, and G protein–coupled receptors (GPCRs), among others (5Davis J.R. Tapon N. Hippo signalling during development.Development. 2019; 146 (31527062): dev16710610.1242/dev.167106Crossref PubMed Scopus (19) Google Scholar, 21Meng Z. Moroishi T. Guan K.-L. Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30 (26728553): 1-1710.1101/gad.274027.115Crossref PubMed Scopus (717) Google Scholar). Despite the diversity of these inputs, each ultimately controls gene expression by regulating the cellular localization of the transcriptional co-factors YAP/TAZ (10Huang J. Wu S. Barrera J. Matthews K. Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP.Cell. 2005; 122 (16096061): 421-43410.1016/j.cell.2005.06.007Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar, 18Dong J. Feldmann G. Huang J. Wu S. Zhang N. Comerford S.A. Gayyed M.F. Anders R.A. Maitra A. Pan D. Elucidation of a universal size-control mechanism in Drosophila and mammals.Cell. 2007; 130 (17889654): 1120-113310.1016/j.cell.2007.07.019Abstract Full Text Full Text PDF PubMed Scopus (1593) Google Scholar, 22Zhang L. Ren F. Zhang Q. Chen Y. Wang B. Jiang J. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control.Dev. Cell. 2008; 14 (18258485): 377-38710.1016/j.devcel.2008.01.006Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar, 23Wu J. Li W. Craddock B.P. Foreman K.W. Mulvihill M.J. Ji Q.-S. Miller W.T. Hubbard S.R. Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.EMBO J. 2008; 27 (18566589): 1985-199410.1038/emboj.2008.116Crossref PubMed Scopus (67) Google Scholar, 24Goulev Y. Fauny J.D. Gonzalez-Marti B. Flagiello D. Silber J. Zider A. SCALLOPED interacts with YORKIE, the nuclear effector of the Hippo tumor-suppressor pathway in Drosophila.Curr. Biol. 2008; 18 (18313299): 435-44110.1016/j.cub.2008.02.034Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 25Oh H. Irvine K.D. In vivo regulation of Yorkie phosphorylation and localization.Development. 2008; 135 (18256197): 1081-108810.1242/dev.015255Crossref PubMed Scopus (298) Google Scholar, 26Oh, H., and Irvine, K. D., (2009) In vivo analysis of Yorkie phosphorylation sites. 28, 1916–1927, 10.1038/onc.2009.43, 19330023.Google Scholar). When the Hippo pathway is inactive, YAP/TAZ translocate to the nucleus and form a transcriptionally competent complex with TEAD. When the pathway is active, YAP/TAZ are phosphorylated, sequestered in the cytoplasm, and degraded. At the heart of the Hippo pathway is a core kinase cassette that includes two kinases that each have two isoforms, MST1/2 (also known as STK3/4 in mammals or Hippo in flies) and LATS1/2 (Warts in flies), and two effector proteins, SAV1 (Salvador in flies) and Mob1 (Mats in flies), which stimulate the activity of each kinase, respectively (Fig. 1A). During signal transduction, an activated MST1/2 phosphorylates and activates Lats1/2, and an active Lats1/2 phosphorylates YAP/TAZ (27Chan E.H.Y. Nousiainen M. Chalamalasetty R.B. Schäfer A. Nigg E.A. Silljé H.H.W. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.Oncogene. 2005; 24 (15688006): 2076-208610.1038/sj.onc.1208445Crossref PubMed Scopus (388) Google Scholar, 28Millward T.A. Hess D. Hemmings B.A. Ndr protein kinase is regulated by phosphorylation on two conserved sequence motifs.J. Biol. Chem. 1999; 274 (10567341): 33847-3385010.1074/jbc.274.48.33847Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 29Stegert M.R. Hergovich A. Tamaskovic R. Bichsel S.J. Hemmings B.A. Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3.Mol. Cell Biol. 2005; 25 (16314523): 11019-1102910.1128/MCB.25.24.11019-11029.2005Crossref PubMed Scopus (124) Google Scholar, 30Hao Y. Chun A. Cheung K. Rashidi B. Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP.J. Biol. Chem. 2008; 283 (18158288): 5496-550910.1074/jbc.M709037200Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar). Signaling through the core kinase cassette begins with activation of MST1/2, a member of the Sterile 20–like kinase family, a kinase that contains an N-terminal kinase domain followed by a disordered linker and coiled-coil domain termed SARAH (Fig. 1A). Active MST1/2 is phosphorylated on the activation loop (Thr-183 for MST1 and Thr-180 for MST2), in an event primarily attributed to trans-autophosphorylation (31Ni L. Li S. Yu J. Min J. Brautigam C.A. Tomchick D.R. Pan D. Luo X. Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5.Structure. 2013; 21 (23972470): 1759-176810.1016/j.str.2013.07.008Abstract Full Text Full Text PDF Scopus (60) Google Scholar, 32Deng Y. Matsui Y. Zhang Y. Lai Z.-C. Hippo activation through homodimerization and membrane association for growth inhibition and organ size control.Dev. Biol. Dev. Biol. 2013; 375 (23298890): 152-15910.1016/j.ydbio.2012.12.017Crossref PubMed Scopus (15) Google Scholar, 33Glantschnig H. Rodan G.A. Reszka A.A. Mapping of MST1 kinase sites of phosphorylation: activation and autophosphorylation.J. Biol. Chem. 2002; 277 (12223493): 42987-4299610.1074/jbc.M208538200Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 34Praskova 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.Biochem. J. 2004; 381 (15109305): 453-46210.1042/BJ20040025Crossref PubMed Scopus (267) Google Scholar) (Fig. 1A). Tao1 kinase can also phosphorylate the activation loop of both MST1 and MST2 but is likely not the primary route of MST1/2 activation (35Boggiano J.C. Vanderzalm P.J. Fehon R.G. Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway.Dev. Cell. 2011; 21 (22075147): 888-89510.1016/j.devcel.2011.08.028Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 36Poon C.L.C. Lin J.I. Zhang X. Harvey K.F. The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway.Dev. Cell. 2011; 21 (22075148): 896-90610.1016/j.devcel.2011.09.012Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). Knockouts of Tao-1 in flies have a milder overgrowth phenotype than knockouts of hippo (35Boggiano J.C. Vanderzalm P.J. Fehon R.G. Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway.Dev. Cell. 2011; 21 (22075147): 888-89510.1016/j.devcel.2011.08.028Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar), and in mammalian cells Tao-1 knockouts do not block MST1/2 activation (37Plouffe S.W. Meng Z. Lin K.C. Lin B. Hong A.W. Chun J.V. Guan K.-L. Characterization of Hippo pathway components by gene inactivation.Mol. Cell. 2016; 64 (27912098): 993-100810.1016/j.molcel.2016.10.034Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). An unresolved question in the field is how multiple signals control the activity of the same core kinase cassette. Whereas multiple events that promote MST1/2 activation have been identified, a common molecular mechanism linking these events to autophosphorylation has not yet been identified. One line of evidence suggests that SARAH domain–mediated homodimerization is required for autophosphorylation (4Zheng Y. Pan D. The Hippo signaling pathway in development and disease.Dev. Cell. 2019; 50 (31386861): 264-28210.1016/j.devcel.2019.06.003Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 31Ni L. Li S. Yu J. Min J. Brautigam C.A. Tomchick D.R. Pan D. Luo X. Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5.Structure. 2013; 21 (23972470): 1759-176810.1016/j.str.2013.07.008Abstract Full Text Full Text PDF Scopus (60) Google Scholar, 32Deng Y. Matsui Y. Zhang Y. Lai Z.-C. Hippo activation through homodimerization and membrane association for growth inhibition and organ size control.Dev. Biol. Dev. 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In cells, lower levels of activation loop phosphorylation are detected for both MST1 variants lacking the SARAH domain and Hippo variants bearing site-specific mutations that weaken SARAH domain homodimerization (38Creasy C.L. Ambrose D.M. Chernoff J. The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain.J. Biol. Chem. 1996; 271 (8702870): 21049-2105310.1074/jbc.271.35.21049Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 39Jin Y. Dong L. Lu Y. Wu W. Hao Q. Zhou Z. Jiang J. Zhao Y. Zhang L. Dimerization and cytoplasmic localization regulate Hippo kinase signaling activity in organ size control.J. Biol. Chem. 2012; 287 (22215676): 5784-579610.1074/jbc.M111.310334Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). In solution, MST2 variants lacking a SARAH domain have little detectable autophosphorylation (31Ni L. Li S. Yu J. Min J. Brautigam C.A. Tomchick D.R. Pan D. Luo X. Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5.Structure. 2013; 21 (23972470): 1759-176810.1016/j.str.2013.07.008Abstract Full Text Full Text PDF Scopus (60) Google Scholar). A set of membrane-associated proteins link external stimuli to the activation and membrane recruitment of the core kinase cassette. External stimuli signal through a set of membrane-associated proteins, NF2 (Merlin in flies) and Kibra, to activate the core kinase cassette (41McCartney B.M. Kulikauskas R.M. LaJeunesse D.R. Fehon R.G. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation.Development. 2000; 127 (10683183): 1315-1324Crossref PubMed Google Scholar, 42Hamaratoglu F. Willecke M. Kango-Singh M. Nolo R. Hyun E. Tao C. Jafar-Nejad H. Halder G. 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• W3091176621 date "2020-11-01" @default.
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