Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP

LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway. LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway. LATS (large tumor suppressor) or warts is a tumor suppressor gene originally isolated in Drosophila as a cell proliferation inhibitor (1Justice R.W. Zilian O. Woods D.F. Noll M. Bryant P.J. Genes Dev. 1995; 9: 534-546Crossref PubMed Scopus (750) Google Scholar, 2Xu T. Wang W. Zhang S. Stewart R.A. Yu W. Development. 1995; 121: 1053-1063Crossref PubMed Google Scholar). Two mammalian homologs of fly LATS, LATS1 and LATS2, were later identified and were shown to be functionally conserved as tumor suppressors by regulating cell cycle progression and apoptosis (3Tao W. Zhang S. Turenchalk G.S. Stewart R.A. St. John M.A. Chen W. Xu T. Nat. Genet. 1999; 21: 177-181Crossref PubMed Scopus (235) Google Scholar, 4St. John M.A. Tao W. Fei X. Fukumoto R. Carcangiu M.L. Brownstein D.G. Parlow A.F. McGrath J. Xu T. Nat. Genet. 1999; 21: 182-186Crossref PubMed Scopus (380) Google Scholar, 5Yabuta N. Fujii T. Copeland N.G. Gilbert D.J. Jenkins N.A. Nishiguchi H. Endo Y. Toji S. Tanaka H. Nishimune Y. Nojima H. Genomics. 2000; 63: 263-270Crossref PubMed Scopus (99) Google Scholar, 6Yang X. Li D.M. Chen W. Xu T. Oncogene. 2001; 20: 6516-6523Crossref PubMed Scopus (112) Google Scholar, 7Li Y. Pei J. Xia H. Ke H. Wang H. Tao W. Oncogene. 2003; 22: 4398-4405Crossref PubMed Scopus (181) Google Scholar, 8Yang X. Yu K.P. Hao Y. Li D.-M. Stewart R. Insogna K. Xu T. Nat. Cell Biol. 2004; 6: 609-617Crossref PubMed Scopus (162) Google Scholar). Most recently, through genetic studies in Drosophila, fly LATS has been identified as a central player in mediating an emerging tumor suppressing pathway called the Hippo-LATS/Warts pathway, including several tumor suppressor genes, fat, merlin, expanded, hippo, RASSF, LATS/warts, salvador, and MATS, and an oncogene called yokie (9Harvey K. Tapon N. Nat. Rev. Cancer. 2007; 7: 182-191Crossref PubMed Scopus (528) Google Scholar, 10Pan D. Genes Dev. 2007; 21: 886-897Crossref PubMed Scopus (535) Google Scholar, 11Saucedo L.J. Edgar B.A. Nat. Rev. Mol. Cell. Biol. 2007; 8: 613-621Crossref PubMed Scopus (296) Google Scholar). LATS/Warts transmits the tumor-suppressing signals from Fat, Merlin, Expanded, RASSF, and Hippo to inhibit cell proliferation and cell growth (cell size) and induces apoptosis by inhibiting oncogene Yokie (Fat → Merlin/Expanded or RASSF → Hippo → LATS/warts/Salvador/MATS → Yokie) (12Harvey K.F. Pfleger C.M. Hariharan I.K. Cell. 2003; 114: 457-467Abstract Full Full PubMed Scopus Google Scholar, M. R. Tao Nat. Cell Biol. 2003; PubMed Scopus Google Scholar, S. J. J. D. Cell. 2003; 114: Full Full PubMed Scopus Google Scholar, J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar, Y. S. R. Nat. Genet. PubMed Scopus Google Scholar, M. M. R. Tao H. Nat. Cell Biol. 8: PubMed Scopus Google Scholar, S. Tapon N. Biol. Full Full PubMed Scopus Google Scholar, Y. Tapon N. H. Biol. Full Full PubMed Scopus Google Scholar, S. Biol. 2007; Full Full PubMed Scopus Google Scholar). and proteins for of LATS/Warts kinase X. T. M. N. Li Y. Cell. Full Full PubMed Scopus Google Scholar, N. K.F. Hariharan I.K. Cell. Full Full PubMed Scopus Google Scholar). mammalian homologs for of the of the Hippo-LATS/Warts for fat, for merlin, for expanded, for RASSF, for hippo, for LATS/warts, for salvador, for MATS, and YAP for and has also been shown that of the mammalian as and function in the as Drosophila X. Li D.M. Chen W. Xu T. Oncogene. 2001; 20: 6516-6523Crossref PubMed Scopus (112) Google Scholar, 7Li Y. Pei J. Xia H. Ke H. Wang H. Tao W. Oncogene. 2003; 22: 4398-4405Crossref PubMed Scopus (181) Google Scholar, T. Cell Biol. 2007; Full Full PubMed Scopus Google Scholar, H. J. Cell 2007; PubMed Scopus Google Scholar, M. Zhang J. Li W. S. PubMed Scopus Google Scholar, W. J. M. D. R. S. Cell. Full Full PubMed Scopus Google Scholar). a Hippo-LATS/Warts pathway and in of LATS that LATS a Ser/Thr kinase that belongs to the kinase of the AGC kinase kinase and and Drosophila and LATS/warts, and mammalian LATS2, and in the regulation of cell cell and and H. B.A. 2007; of Google Scholar). Although has been shown that the kinase is for the of X. Li D.M. Chen W. Xu T. Oncogene. 2001; 20: 6516-6523Crossref PubMed Scopus (112) Google Scholar, 7Li Y. Pei J. Xia H. Ke H. Wang H. Tao W. Oncogene. 2003; 22: 4398-4405Crossref PubMed Scopus (181) Google Scholar, Y. T. T. J. Biol. 2003; Full Full PubMed Scopus Google Scholar, K. Y. Cell. 2004; Full Full PubMed Scopus Google Scholar, H. Pei J. Xia H. H. Woods T. Tao W. Cell 2004; PubMed Scopus Google Scholar, S. B.A. Mol. Cell. 2007; Full Full PubMed Scopus Google downstream kinase substrates largely unknown. of substrates and of will be to the molecular mechanism of Yokie identified as a kinase and downstream target of Drosophila Drosophila LATS can cell proliferation and cell growth by and inhibiting Yokie function J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar). the molecular mechanism by LATS and inactivates Yokie unknown. the of identified as an oncogene in and M. Zhang J. Li W. S. PubMed Scopus Google Scholar, W. J. M. D. R. S. Cell. Full Full PubMed Scopus Google Scholar). of YAP of and tumor in mice M. Zhang J. Li W. S. PubMed Scopus Google Scholar, W. J. M. D. R. S. Cell. Full Full PubMed Scopus Google Scholar). and LATS1 and phosphorylate and YAP function to be In YAP identified as a transcription and oncogene in mammalian the downstream genes by YAP have been In this study, we have discovered that LATS1 can and phosphorylate YAP in vitro and in vivo. Significantly, we have provided convincing evidence that LATS1 can transcription regulation and of YAP by inhibiting its via phosphorylation of in YAP. using kinase we have also identified the consensus phosphorylation sequence for LATS1 and kinase substrates. findings that LATS/Ndr has to of AGC kinase and of LATS1 YAP or were and and Drosophila kinase and or by by and the of were for is and is in and is is and is in and is is and is in and is by using the to the or by and and Drosophila kinase Cell and cell and as X. Yu K.P. Hao Y. Li D.-M. Stewart R. Insogna K. Xu T. Nat. Cell Biol. 2004; 6: 609-617Crossref PubMed Scopus (162) Google Scholar). were a and the in this were by to and cell were and to and YAP were from from cell and and were as X. Yu K.P. Hao Y. Li D.-M. Stewart R. Insogna K. Xu T. Nat. Cell Biol. 2004; 6: 609-617Crossref PubMed Scopus (162) Google Scholar, X. Hao Y. Oncogene. PubMed Scopus Google Scholar). and proteins were and as X. Yu K.P. Hao Y. Li D.-M. Stewart R. Insogna K. Xu T. Nat. Cell Biol. 2004; 6: 609-617Crossref PubMed Scopus (162) Google Scholar). the of or of or LATS1 or YAP proteins on and for were and in and and the were to and using or and were on a and of or or were of and of and of for the of of to gene after Two after the were through a and using a were of a after and a of were and were a and of to the (cell the of of of or were of a to after cell were and or LATS1 of a of of Two after the were for or microarray or to be for of a LATS1 or and a sequence in the were from of using to the and of LATS1 and by of YAP after LATS were a of a a were to using after were and in a were or a of of in of a were YAP Two after were to a using an of is by on and microarray analysis, of were or and the to the were and for as the of or were and to a for in a microarray were and on an were the YAP up-regulated and down-regulated genes were to the genes transcription or in of a of were in on the and a gene were to the of for to the of gene identified from microarray In of of from or YAP were and and in cycle of for for and of for for and for using an sequence as of in of gene in to that in as the cellular gene and were from of for or or or were in and inhibitor an in vitro of of and for were for and were of substrates in a kinase of and for by of for and to the proteins were to a for of and to for phosphorylation of YAP by LATS1 in or were as of cell or of for and to using in vitro kinase the and were a of in a kinase and for on a and and to as kinase of is as the of for this to the for and of and proteins and were as X. Yu K.P. Hao Y. Li D.-M. Stewart R. Insogna K. Xu T. Nat. Cell Biol. 2004; 6: 609-617Crossref PubMed Scopus (162) Google Scholar, X. Hao Y. Oncogene. PubMed Scopus Google Scholar). were using the in the of LATS1 and YAP in and in to LATS1 YAP in vivo. LATS1 and YAP were or cell were in the the that LATS1 YAP is to of in the we also the of LATS1 YAP in of LATS1 and YAP. LATS1 in the we a to LATS1 YAP in to bind to in vitro We also of the kinase in LATS2, and YAP. to bind to and were to that LATS1 and the of the kinase in that YAP. LATS and conserved in kinase this that LATS YAP its this and the molecular mechanism of we to the in LATS and YAP for YAP belongs to of the proteins that bind through to or in K. S. Yu J. K. J. M. Chen R. W. T. Mol. Cell. Biol. PubMed Scopus Google Scholar). 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Rev. Mol. Cell. Biol. 2007; 8: PubMed Scopus Google Scholar). Ndr/LATS as and were also to phosphorylate YAP in vitro we the consensus phosphorylation the phosphorylation for to the we can that the consensus phosphorylation sequence for LATS/Ndr kinase substrates is HX(R/H/K)XX(S/T) We an of LATS/Ndr consensus phosphorylation of of the AGC kinase of the consensus Most of the AGC to for In of the consensus phosphorylation for AGC kinase substrates an the or LATS/Ndr is the kinase in the AGC kinase that has in its consensus phosphorylation sequence the and of YAP by LATS1 studies that phosphorylation of YAP its S. M. J. Mol. Cell. 2003; Full Full PubMed Scopus Google Scholar). phosphorylation of YAP by LATS also its we or or a R. Chen K. Y. Y. J. 1999; PubMed Scopus Google YAP in the cytoplasm and Although of LATS1 can YAP in the cytoplasm of LATS1 YAP in the cytoplasm in of the the a YAP mutant LATS1 phosphorylation in the and after of in the These that the phosphorylation of YAP by LATS1 its the We also of LATS1 of YAP by of or LATS1 and by from the YAP YAP in cytoplasm and of of YAP in the and and in the cytoplasm and We have also LATS of YAP. after of LATS and in the YAP originally in cytoplasm and the These demonstrate that phosphorylation of YAP by LATS1 its to the to sequestration of YAP in the of Genes by YAP by Drosophila, identified as an oncogene that cell proliferation and apoptosis by of and transcription J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar). mammalian YAP also identified as an and of YAP of mammalian YAP has on the of and M. Zhang J. Li W. S. PubMed Scopus Google that the downstream genes mediating in be from in the cellular genes up-regulated or down-regulated by YAP of we or also by and as a for shown by of of were by of by YAP a in YAP and and Although as and a called the genes by we from and and an using the In this many cellular genes have on of signals from of the for gene and and using for up-regulated and down-regulated genes cell proliferation, cell cell cell and have been identified and in We to of the genes after of YAP. of genes identified in microarray as genes were also by a YAP in of the up-regulated genes is the gene that up-regulated by YAP. or as and were also after of YAP YAP originally identified as a transcription the transcription of of the tumor as and a of the growth were down-regulated by YAP of cellular genes up-regulated and down-regulated by genes transcription cell cycle growth proliferation, cell growth proliferation, cell proliferation, cell proliferation, cell cell cell cell cell proliferation, cell growth proliferation, cell kinase proliferation proliferation, cell genes proliferation proliferation kinase inhibitor proliferation proliferation, cell proliferation, cell proliferation, cell proliferation proliferation, cell proliferation proliferation, cell inhibitor proliferation, cell in a of and Cell by has been shown that of Drosophila LATS cell proliferation and induces apoptosis by inhibiting Yokie J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar). demonstrate that LATS1 can phosphorylate YAP and inhibit its to the that phosphorylation of YAP by LATS1 its transcription regulation of cellular genes in the this we LATS1 and of for genes by including and that of transcription or of cellular genes We also LATS1 can inhibit cell using shown in and on for that that of YAP cell as shown by the of many on and of LATS1 cell of LATS1 cell and the LATS phosphorylation and to or and Although tremendous progress has been made toward our understanding the emerging Hippo-LATS/Warts tumor suppressor pathway in the regulation of cell growth, cell proliferation, and cell in Drosophila, is this pathway in In this study, we have provided convincing evidence that LATS1 is a regulator of LATS1 can inhibit transcription regulation and cell of our YAP also recently to be by Drosophila LATS/Warts and through phosphorylation and to roles in the regulation of and cell J. J. S. Zhang N. R.A. D. Cell. 2007; Full Full PubMed Scopus Google Scholar, X. Li W. J. J. T. Yu J. Li K. Genes Dev. 2007; 21: PubMed Scopus Google Scholar). the that can phosphorylate and M. Oncogene. PubMed Scopus Google we can that of the Hippo-LATS/Warts pathway, → → is conserved in Drosophila and LATS is the central player in the Hippo-LATS/Warts pathway. studies have shown that fly and mammalian in by regulating cell proliferation, cell growth, and apoptosis X. Li D.M. Chen W. Xu T. Oncogene. 2001; 20: 6516-6523Crossref PubMed Scopus (112) Google Scholar, 7Li Y. Pei J. Xia H. Ke H. Wang H. Tao W. Oncogene. 2003; 22: 4398-4405Crossref PubMed Scopus (181) Google Scholar, S. J. J. D. Cell. 2003; 114: Full Full PubMed Scopus Google Scholar, N. K.F. Hariharan I.K. Cell. Full Full PubMed Scopus Google Scholar). the by LATS suppresses tumor growth LATS is a kinase and the kinase is for its tumor suppressing and X. Li D.M. Chen W. Xu T. Oncogene. 2001; 20: 6516-6523Crossref PubMed Scopus (112) Google Scholar, 7Li Y. Pei J. Xia H. Ke H. Wang H. Tao W. Oncogene. 2003; 22: 4398-4405Crossref PubMed Scopus (181) Google Scholar, Y. T. T. J. Biol. 2003; Full Full PubMed Scopus Google Scholar, K. Y. Cell. 2004; Full Full PubMed Scopus Google Scholar, H. Pei J. Xia H. H. Woods T. Tao W. Cell 2004; PubMed Scopus Google Scholar, S. B.A. Mol. Cell. 2007; Full Full PubMed Scopus Google of the kinase substrates of LATS is to the and of Yokie is the identified as the of LATS kinase in Drosophila J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar). LATS phosphorylation Yokie and mammalian and homologs also phosphorylate the mammalian Yokie to be In this study, we have shown for the that LATS1 and can and phosphorylate YAP in vitro and in LATS homologs and were to bind to YAP and phosphorylate YAP in We have also the in LATS1 and YAP for We that the in LATS1 and in YAP for that is in LATS1 this is conserved and be in LATS, as or Drosophila is that the this from to YAP. the sequence of we LATS bind to YAP. the kinase of LATS has to that of that phosphorylate the and were to phosphorylate YAP in to were to phosphorylate YAP in vivo. LATS1 and LATS2, and the YAP. Although Yokie to be by Drosophila LATS, the phosphorylation in Yokie have been identified J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar). of phosphorylation in is to roles in the Hippo-LATS/Warts pathway. a of and we have identified phosphorylation the in YAP. of phosphorylation also conserved in Drosophila using a kinase we have also identified the consensus phosphorylation for and kinase substrates. a of LATS, to phosphorylate the J. M. M. 6: PubMed Scopus Google of our consensus phosphorylation These findings that of the of LATS/Ndr kinase in have the phosphorylation for proteins this using on the we were to many substrates of LATS/Ndr this is the kinase identified for of the consensus phosphorylation sequence will our to kinase substrates of Ndr/LATS that be in mediating the emerging Hippo-LATS/Warts pathway and various as tumor and this consensus phosphorylation sequence is to of AGC kinase to the of consensus phosphorylation many of the AGC kinase can phosphorylate the and AGC were to phosphorylate on the phosphorylation K. H. S. M. 2007; PubMed Scopus Google Scholar). LATS and and the kinase that have the and of its consensus phosphorylation the of the consensus phosphorylation is for substrates to be and have a that is in AGC kinases. have an of and of the kinase from AGC and also be kinase of LATS has been identified of the phosphorylation in also to be by AGC Nat. Rev. Mol. Cell. Biol. 2007; 8: PubMed Scopus Google Scholar). has a consensus phosphorylation Although substrates have been identified for Cell. 2007; Full Full PubMed Scopus Google YAP is the that has the phosphorylation Nat. Rev. Mol. Cell. Biol. 2007; 8: PubMed Scopus Google Scholar). We also the of LATS/Ndr and as in AGC kinases. kinase demonstrate that the in the is and that of the consensus phosphorylation its phosphorylation by and LATS/Ndr and substrates. Although our findings and the shown in Drosophila genetic studies that YAP is the of LATS, to be is also the kinase YAP in our Although to be by Drosophila LATS, the of this phosphorylation for function is unknown. In this study, we provided convincing evidence that phosphorylation of YAP by LATS1 YAP in the from as a transcription regulator in the of of YAP in the of phosphorylation in YAP YAP to be in the and to a on its to the of LATS1 on phosphorylation of in YAP by kinase its to the to transcription R. Y. G.S. J. 2004; PubMed Scopus Google Scholar). phosphorylation of YAP a in regulating its in YAP has been shown to be the for Nat. Rev. Mol. Cell. Biol. 2007; 8: PubMed Scopus Google Scholar). is that phosphorylation of YAP by LATS1 its to be phosphorylation of of the phosphorylation of YAP by LATS1 is for the of YAP Drosophila and mammalian has been identified as an oncogene for J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar, M. Zhang J. Li W. S. PubMed Scopus Google Scholar, W. J. M. D. R. S. Cell. Full Full PubMed Scopus Google Scholar). of cell proliferation, and tumor in Drosophila and mice and of J. S. J. K. D. Cell. Full Full PubMed Scopus Google Scholar, M. Zhang J. Li W. S. PubMed Scopus Google Scholar). In our studies and also that of YAP many cellular as of and an in cell and the of Hao and X. M. Zhang J. Li W. S. PubMed Scopus Google of the for tumor Although of cycle and transcription has been to be for Drosophila tumor of and for of the by of in Drosophila L.J. Edgar B.A. Nat. Rev. Mol. Cell. Biol. 2007; 8: 613-621Crossref PubMed Scopus (296) Google Scholar). In mammalian has been shown that cycle and after of YAP M. Zhang J. Li W. S. PubMed Scopus Google Scholar). Although YAP originally identified as a transcription and many transcription as and S. M. J. Mol. Cell. 2003; Full Full PubMed Scopus Google Scholar, S. M. Y. M. M. J. Biol. 2001; Full Full PubMed Scopus Google Scholar, X. M. J. Biol. 2001; Full Full PubMed Scopus Google Scholar, H. Y. M.L. Genes Dev. 2001; PubMed Scopus Google the downstream genes mediating cell and many cellular as remain to be using the we have identified many genes by YAP. These genes in the regulation of cell proliferation, cell cell and cell and by YAP growth that cell proliferation, cell and J. Rev. PubMed Scopus Google Scholar, R. 8: PubMed Scopus Google that YAP growth transcription to cell we have also that of YAP induces a of the proteins for cell cell and cell proliferation and cell J. 2003; PubMed Scopus Google Scholar, Cell. Full Full PubMed Scopus Google Scholar). It has been shown that of growth and of of in growth and tumor in mice PubMed Scopus Google Scholar). is a cell in and in in J. 2003; PubMed Scopus Google Scholar). has also been shown to be in and of J. 2003; PubMed Scopus Google Scholar). is in has been is the that is in after cell be a downstream mediating growth and of It will be to of can also or of in can growth and or cellular we have also identified many genes by YAP. These genes of cell proliferation or tumor and have been shown to be tumor suppressors that inhibit tumor cell proliferation and tumor and apoptosis Cell Mol. 2001; PubMed Google Scholar, K. 2004; PubMed Scopus Google has been shown to cell proliferation and tumor and N. S. S. PubMed Scopus Google Scholar). of genes by YAP will cell proliferation and cell and of In has also been shown that of YAP of transcription R. Y. G.S. J. 2004; PubMed Scopus Google Scholar). YAP also cell and cell proliferation and tumor by inhibiting transcription of several of cell proliferation and cell and of Most our studies that mammalian and Drosophila can tumor by regulating transcription of downstream genes, to function as of downstream genes of YAP will have on our understanding the pathway of this emerging Hippo-LATS/Warts pathway In we have provided convincing evidence that tumor suppressor LATS is a regulator of oncogene YAP. LATS1 inactivates YAP oncogenic function by its the to cellular genes for cell proliferation, cell and cell Most by using YAP phosphorylation as a we were to HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence of the LATS/Ndr kinase the that the Hippo-LATS/Warts tumor suppressor pathway and Ndr/LATS in also in various our research findings will have a profound on our understanding of the molecular mechanism and the pathway We for the for the microarray for the microarray and for of the

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