In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity.

Department of Cell and Developmental Biology Institute of Molecular Genetics of the CAS v v i Videnska 1083 142 20 Prague 4 Czech Republic

Zobrazit více v PubMed

Molenaar M., van de Wetering M., Oosterwegel M., Peterson-Maduro J., Godsave S., Korinek V., Roose J., Destree O., Clevers H. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in xenopus embryos. Cell. 1996;86:391–399. doi: 10.1016/S0092-8674(00)80112-9. PubMed DOI

Behrens J., von Kries J.P., Kuhl M., Bruhn L., Wedlich D., Grosschedl R., Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996;382:638–642. doi: 10.1038/382638a0. PubMed DOI

Huber O., Korn R., McLaughlin J., Ohsugi M., Herrmann B.G., Kemler R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech. Dev. 1996;59:3–10. doi: 10.1016/0925-4773(96)00597-7. PubMed DOI

Korinek V., Barker N., Morin P.J., vanWichen D., deWeger R., Kinzler K.W., Vogelstein B., Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science. 1997;275:1784–1787. doi: 10.1126/science.275.5307.1784. PubMed DOI

Morin P.J., Sparks A.B., Korinek V., Barker N., Clevers H., Vogelstein B., Kinzler K.W. Activation of beta-catenin-Tcf signalling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–1790. doi: 10.1126/science.275.5307.1787. PubMed DOI

Rubinfeld B., Robbins P., El-Gamil M., Albert I., Porfiri E., Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science. 1997;275:1790–1792. doi: 10.1126/science.275.5307.1790. PubMed DOI

Korinek V., Barker N., Moerer P., van Donselaar E., Huls G., Peters P.J., Clevers H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 1998;19:379–383. PubMed

Sato T., Vries R.G., Snippert H.J., van de Wetering M., Barker N., Stange D.E., van Es J.H., Abo A., Kujala P., Peters P.J., et al. Single LGR5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–265. doi: 10.1038/nature07935. PubMed DOI

de Lau W., Barker N., Low T.Y., Koo B.K., Li V.S., Teunissen H., Kujala P., Haegebarth A., Peters P.J., van de Wetering M., et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476:293–297. doi: 10.1038/nature10337. PubMed DOI

Koo B.K., Spit M., Jordens I., Low T.Y., Stange D.E., van de Wetering M., van Es J.H., Mohammed S., Heck A.J., Maurice M.M., et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012;488:665–669. doi: 10.1038/nature11308. PubMed DOI

Camargo 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;17:2054–2060. doi: 10.1016/j.cub.2007.10.039. PubMed DOI

Azzolin L., Panciera T., Soligo S., Enzo E., Bicciato S., Dupont S., Bresolin S., Frasson C., Basso G., Guzzardo V., et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158:157–170. doi: 10.1016/j.cell.2014.06.013. PubMed DOI

Azzolin L., Zanconato F., Bresolin S., Forcato M., Basso G., Bicciato S., Cordenonsi M., Piccolo S. Role of TAZ as mediator of Wnt signalling. Cell. 2012;151:1443–1456. doi: 10.1016/j.cell.2012.11.027. PubMed DOI

Park H.W., Kim Y.C., Yu B., Moroishi T., Mo J.S., Plouffe S.W., Meng Z., Lin K.C., Yu F.X., Alexander C.M., et al. Alternative Wnt signalling activates YAP/TAZ. Cell. 2015;162:780–794. doi: 10.1016/j.cell.2015.07.013. PubMed DOI PMC

Planas-Paz L., Orsini V., Boulter L., Calabrese D., Pikiolek M., Nigsch F., Xie Y., Roma G., Donovan A., Marti P., et al. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nat. Cell Biol. 2016;18:467–479. doi: 10.1038/ncb3337. PubMed DOI

Luo J., Yang Z., Ma Y., Yue Z., Lin H., Qu G., Huang J., Dai W., Li C., Zheng C., et al. Lgr4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat. Med. 2016;22:539–546. doi: 10.1038/nm.4076. PubMed DOI

Clevers H. Stem cells. What is an adult stem cell? Science. 2015;350:1319–1320. doi: 10.1126/science.aad7016. PubMed DOI

Jones D.L., Wagers A.J. No place like home: Anatomy and function of the stem cell niche. Nat. Rev. Mol. Cell Biol. 2008;9:11–21. doi: 10.1038/nrm2319. PubMed DOI

Barker N. Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regeneration. Nat. Rev. Mol. Cell Biol. 2014;15:19–33. doi: 10.1038/nrm3721. PubMed DOI

van de Wetering M., Sancho E., Verweij C., de Lau W., Oving I., Hurlstone A., van der Horn K., Batlle E., Coudreuse D., Haramis A.P., et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002;111:241–250. doi: 10.1016/S0092-8674(02)01014-0. PubMed DOI

Van der Flier L.G., Sabates-Bellver J., Oving I., Haegebarth A., De Palo M., Anti M., Van Gijn M.E., Suijkerbuijk S., Van de Wetering M., Marra G., et al. The intestinal Wnt/TCF signature. Gastroenterology. 2007;132:628–632. doi: 10.1053/j.gastro.2006.08.039. PubMed DOI

Barker N., van Es J.H., Kuipers J., Kujala P., van den Born M., Cozijnsen M., Haegebarth A., Korving J., Begthel H., Peters P.J., et al. Identification of stem cells in small intestine and colon by marker gene LGR5. Nature. 2007;449:1003–1007. doi: 10.1038/nature06196. PubMed DOI

Clevers H.C., Bevins C.L. Paneth cells: Maestros of the small intestinal crypts. Annu. Rev. Physiol. 2013;75:289–311. doi: 10.1146/annurev-physiol-030212-183744. PubMed DOI

van der Flier L.G., Haegebarth A., Stange D.E., van de Wetering M., Clevers H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology. 2009;137:15–17. doi: 10.1053/j.gastro.2009.05.035. PubMed DOI

Munoz J., Stange D.E., Schepers A.G., van de Wetering M., Koo B.K., Itzkovitz S., Volckmann R., Kung K.S., Koster J., Radulescu S., et al. The LGR5 intestinal stem cell signature: Robust expression of proposed quiescent ‘+4’ cell markers. EMBO J. 2012;31:3079–3091. doi: 10.1038/emboj.2012.166. PubMed DOI PMC

Fafilek B., Krausova M., Vojtechova M., Pospichalova V., Tumova L., Sloncova E., Huranova M., Stancikova J., Hlavata A., Svec J., et al. Troy, a tumour necrosis factor receptor family member, interacts with LGR5 to inhibit Wnt signalling in intestinal stem cells. Gastroenterology. 2013;144:381–391. doi: 10.1053/j.gastro.2012.10.048. PubMed DOI

Sasaki N., Sachs N., Wiebrands K., Ellenbroek S.I., Fumagalli A., Lyubimova A., Begthel H., van den Born M., van Es J.H., Karthaus W.R., et al. Reg4+ deep crypt secretory cells function as epithelial niche for LGR5+ stem cells in colon. Proc. Natl. Acad. Sci. USA. 2016;113:E5399–E5407. doi: 10.1073/pnas.1607327113. PubMed DOI PMC

Potten C.S., Booth C., Pritchard D.M. The intestinal epithelial stem cell: The mucosal governor. Int. J. Exp. Pathol. 1997;78:219–243. doi: 10.1046/j.1365-2613.1997.280362.x. PubMed DOI PMC

Tian H., Biehs B., Warming S., Leong K.G., Rangell L., Klein O.D., de Sauvage F.J. A reserve stem cell population in small intestine renders LGR5-positive cells dispensable. Nature. 2011;478:255–259. doi: 10.1038/nature10408. PubMed DOI PMC

Itzkovitz S., Lyubimova A., Blat I.C., Maynard M., van Es J., Lees J., Jacks T., Clevers H., van Oudenaarden A. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat. Cell Biol. 2012;14:106–114. doi: 10.1038/ncb2384. PubMed DOI PMC

Asfaha S., Hayakawa Y., Muley A., Stokes S., Graham T.A., Ericksen R.E., Westphalen C.B., von Burstin J., Mastracci T.L., Worthley D.L., et al. Krt19+/LGR5− cells are radioresistant cancer-initiating stem cells in the colon and intestine. Cell Stem Cell. 2015;16:627–638. doi: 10.1016/j.stem.2015.04.013. PubMed DOI PMC

Tetteh P.W., Basak O., Farin H.F., Wiebrands K., Kretzschmar K., Begthel H., van den Born M., Korving J., de Sauvage F., van Es J.H., et al. Replacement of lost LGR5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell. 2016;18:203–213. doi: 10.1016/j.stem.2016.01.001. PubMed DOI

Buczacki S.J., Zecchini H.I., Nicholson A.M., Russell R., Vermeulen L., Kemp R., Winton D.J. Intestinal label-retaining cells are secretory precursors expressing LGR5. Nature. 2013;495:65–69. doi: 10.1038/nature11965. PubMed DOI

Meran L., Baulies A., Li V.S.W. Intestinal stem cell niche: The extracellular matrix and cellular components. Stem Cells Int. 2017;2017 doi: 10.1155/2017/7970385. PubMed DOI PMC

Sato T., van Es J.H., Snippert H.J., Stange D.E., Vries R.G., van den Born M., Barker N., Shroyer N.F., van de Wetering M., Clevers H. Paneth cells constitute the niche for LGR5 stem cells in intestinal crypts. Nature. 2011;469:415–418. doi: 10.1038/nature09637. PubMed DOI PMC

Farin H.F., Van Es J.H., Clevers H. Redundant sources of wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology. 2012;143:1518–1529. doi: 10.1053/j.gastro.2012.08.031. PubMed DOI

Kim T.H., Escudero S., Shivdasani R.A. Intact function of LGR5 receptor-expressing intestinal stem cells in the absence of Paneth cells. Proc. Natl. Acad. Sci. USA. 2012;109:3932–3937. doi: 10.1073/pnas.1113890109. PubMed DOI PMC

Kabiri Z., Greicius G., Madan B., Biechele S., Zhong Z., Zaribafzadeh H., Edison, Aliyev J., Wu Y., Bunte R., et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development. 2014;141:2206–2215. doi: 10.1242/dev.104976. PubMed DOI

van Amerongen R., Nusse R. Towards an integrated view of Wnt signalling in development. Development. 2009;136:3205–3214. doi: 10.1242/dev.033910. PubMed DOI

Willert K., Brown J.D., Danenberg E., Duncan A.W., Weissman I.L., Reya T., Yates J.R., 3rd, Nusse R. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–452. doi: 10.1038/nature01611. PubMed DOI

Takada R., Satomi Y., Kurata T., Ueno N., Norioka S., Kondoh H., Takao T., Takada S. Monounsaturated fatty acid modification of Wnt protein: Its role in Wnt secretion. Dev. Cell. 2006;11:791–801. doi: 10.1016/j.devcel.2006.10.003. PubMed DOI

Doubravska L., Krausova M., Gradl D., Vojtechova M., Tumova L., Lukas J., Valenta T., Pospichalova V., Fafilek B., Plachy J., et al. Fatty acid modification of Wnt1 and Wnt3a at serine is prerequisite for lipidation at cysteine and is essential for Wnt signalling. Cell. Signal. 2011;23:837–848. doi: 10.1016/j.cellsig.2011.01.007. PubMed DOI

Langton P.F., Kakugawa S., Vincent J.P. Making, exporting and modulating Wnts. Trends Cell Biol. 2016;26:756–765. doi: 10.1016/j.tcb.2016.05.011. PubMed DOI

Gregorieff A., Pinto D., Begthel H., Destree O., Kielman M., Clevers H. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology. 2005;129:626–638. doi: 10.1016/j.gastro.2005.06.007. PubMed DOI

Flanagan D.J., Phesse T.J., Barker N., Schwab R.H., Amin N., Malaterre J., Stange D.E., Nowell C.J., Currie S.A., Saw J.T., et al. Frizzled7 functions as a Wnt receptor in intestinal epithelial LGR5+ stem cells. Stem Cell Rep. 2015;4:759–767. doi: 10.1016/j.stemcr.2015.03.003. PubMed DOI PMC

Ueno K., Hazama S., Mitomori S., Nishioka M., Suehiro Y., Hirata H., Oka M., Imai K., Dahiya R., Hinoda Y. Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells. Br. J. Cancer. 2009;101:1374–1381. doi: 10.1038/sj.bjc.6605307. PubMed DOI PMC

Valenta T., Hausmann G., Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31:2714–2736. doi: 10.1038/emboj.2012.150. PubMed DOI PMC

Hrckulak D., Kolar M., Strnad H., Korinek V. TCF/LEF transcription factors: An update from the internet resources. Cancers. 2016;8:70. doi: 10.3390/cancers8070070. PubMed DOI PMC

Stamos J.L., Weis W.I. The beta-catenin destruction complex. Cold Spring Harb. Perspect. Biol. 2013;5:a007898. doi: 10.1101/cshperspect.a007898. PubMed DOI PMC

Tortelote G.G., Reis R.R., de Almeida Mendes F., Abreu J.G. Complexity of the Wnt/beta-catenin pathway: Searching for an activation model. Cell. Signal. 2017;40:30–43. doi: 10.1016/j.cellsig.2017.08.008. PubMed DOI

Kuhnert F., Davis C.R., Wang H.T., Chu P., Lee M., Yuan J., Nusse R., Kuo C.J. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl. Acad. Sci. USA. 2004;101:266–271. doi: 10.1073/pnas.2536800100. PubMed DOI PMC

Nakamura Y., Nishisho I., Kinzler K.W., Vogelstein B., Miyoshi Y., Miki Y., Ando H., Horii A., Nagase H. Mutations of the adenomatous polyposis coli gene in familial polyposis coli patients and sporadic colorectal tumors. Princess Takamatsu Symp. 1991;22:285–292. doi: 10.1620/tjem.168.141. PubMed DOI

Powell S.M., Zilz N., Beazer-Barclay Y., Bryan T.M., Hamilton S.R., Thibodeau S.N., Vogelstein B., Kinzler K.W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992;359:235–237. doi: 10.1038/359235a0. PubMed DOI

Bright-Thomas R.M., Hargest R. APC, beta-catenin and hTCF-4; an unholy trinity in the genesis of colorectal cancer. Eur. J. Surg. Oncol. 2003;29:107–117. doi: 10.1053/ejso.2002.1331. PubMed DOI

Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. PubMed PMC

Moser A.R., Pitot H.C., Dove W.F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990;247:322–324. doi: 10.1126/science.2296722. PubMed DOI

Su L.K., Kinzler K.W., Vogelstein B., Preisinger A.C., Moser A.R., Luongo C., Gould K.A., Dove W.F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992;256:668–670. doi: 10.1126/science.1350108. PubMed DOI

Barker N., Ridgway R.A., van Es J.H., van de Wetering M., Begthel H., van den Born M., Danenberg E., Clarke A.R., Sansom O.J., Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–611. doi: 10.1038/nature07602. PubMed DOI

Mazzoni S.M., Petty E.M., Stoffel E.M., Fearon E.R. An AXIN2 mutant allele associated with predisposition to colorectal neoplasia has context-dependent effects on AXIN2 protein function. Neoplasia. 2015;17:463–472. doi: 10.1016/j.neo.2015.04.006. PubMed DOI PMC

Davies P.S., Dismuke A.D., Powell A.E., Carroll K.H., Wong M.H. Wnt-reporter expression pattern in the mouse intestine during homeostasis. BMC Gastroenterol. 2008;8:57. doi: 10.1186/1471-230X-8-57. PubMed DOI PMC

Farin H.F., Jordens I., Mosa M.H., Basak O., Korving J., Tauriello D.V., de Punder K., Angers S., Peters P.J., Maurice M.M., et al. Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature. 2016;530:340–343. doi: 10.1038/nature16937. PubMed DOI

Simons M., Mlodzik M. Planar cell polarity signaling: From fly development to human disease. Annu. Rev. Genet. 2008;42:517–540. doi: 10.1146/annurev.genet.42.110807.091432. PubMed DOI PMC

De A. Wnt/Ca2+ signaling pathway: A brief overview. Acta Biochim. Biophys. Sin. (Shanghai) 2011;43:745–756. doi: 10.1093/abbs/gmr079. PubMed DOI

Mehdawi L.M., Prasad C.P., Ehrnstrom R., Andersson T., Sjolander A. Non-canonical WNT5A signaling up-regulates the expression of the tumor suppressor 15-PGDH and induces differentiation of colon cancer cells. Mol. Oncol. 2016;10:1415–1429. doi: 10.1016/j.molonc.2016.07.011. PubMed DOI PMC

Ali I., Medegan B., Braun D.P. Wnt9A induction linked to suppression of human colorectal cancer cell proliferation. Int. J. Mol. Sci. 2016;17:495. doi: 10.3390/ijms17040495. PubMed DOI PMC

Bakker E.R., Das A.M., Helvensteijn W., Franken P.F., Swagemakers S., van der Valk M.A., ten Hagen T.L., Kuipers E.J., van Veelen W., Smits R. Wnt5a promotes human colon cancer cell migration and invasion but does not augment intestinal tumorigenesis in Apc1638N mice. Carcinogenesis. 2013;34:2629–2638. doi: 10.1093/carcin/bgt215. PubMed DOI

Yoon J.K., Lee J.S. Cellular signaling and biological functions of R-spondins. Cell. Signal. 2012;24:369–377. doi: 10.1016/j.cellsig.2011.09.023. PubMed DOI PMC

Wei Q., Yokota C., Semenov M.V., Doble B., Woodgett J., He X. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. J. Biol. Chem. 2007;282:15903–15911. doi: 10.1074/jbc.M701927200. PubMed DOI

Carmon K.S., Gong X., Lin Q., Thomas A., Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc. Natl. Acad. Sci. USA. 2011;108:11452–11457. doi: 10.1073/pnas.1106083108. PubMed DOI PMC

Glinka A., Dolde C., Kirsch N., Huang Y.L., Kazanskaya O., Ingelfinger D., Boutros M., Cruciat C.M., Niehrs C. LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Rep. 2011;12:1055–1061. doi: 10.1038/embor.2011.175. PubMed DOI PMC

Ruffner H., Sprunger J., Charlat O., Leighton-Davies J., Grosshans B., Salathe A., Zietzling S., Beck V., Therier M., Isken A., et al. R-spondin potentiates Wnt/beta-catenin signaling through orphan receptors LGR4 and LGR5. PLoS ONE. 2012;7:e40976. doi: 10.1371/journal.pone.0040976. PubMed DOI PMC

de Lau W., Peng W.C., Gros P., Clevers H. The R-spondin/LGR5/RNF43 module: Regulator of Wnt signal strength. Genes Dev. 2014;28:305–316. doi: 10.1101/gad.235473.113. PubMed DOI PMC

Xie Y., Zamponi R., Charlat O., Ramones M., Swalley S., Jiang X., Rivera D., Tschantz W., Lu B., Quinn L., et al. Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO Rep. 2013;14:1120–1126. doi: 10.1038/embor.2013.167. PubMed DOI PMC

Zebisch M., Xu Y., Krastev C., MacDonald B.T., Chen M., Gilbert R.J., He X., Jones E.Y. Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat. Commun. 2013;4:2787. doi: 10.1038/ncomms3787. PubMed DOI PMC

Loregger A., Grandl M., Mejias-Luque R., Allgauer M., Degenhart K., Haselmann V., Oikonomou C., Hatzis P., Janssen K.P., Nitsche U., et al. The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated beta-catenin by sequestering TCF4 to the nuclear membrane. Sci. Signal. 2015;8:ra90. doi: 10.1126/scisignal.aac6757. PubMed DOI

Carmon K.S., Gong X., Yi J., Thomas A., Liu Q. RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling. Proc. Natl. Acad. Sci. USA. 2014;111:E1221–E1229. doi: 10.1073/pnas.1323106111. PubMed DOI PMC

Jiang X., Charlat O., Zamponi R., Yang Y., Cong F. Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol. Cell. 2015;58:522–533. doi: 10.1016/j.molcel.2015.03.015. PubMed DOI

Sansom O.J., Reed K.R., Hayes A.J., Ireland H., Brinkmann H., Newton I.P., Batlle E., Simon-Assmann P., Clevers H., Nathke I.S., et al. Loss of APC in vivo immediately perturbs Wnt signaling, differentiation and migration. Genes Dev. 2004;18:1385–1390. doi: 10.1101/gad.287404. PubMed DOI PMC

Yan K.S., Janda C.Y., Chang J., Zheng G.X.Y., Larkin K.A., Luca V.C., Chia L.A., Mah A.T., Han A., Terry J.M., et al. Non-equivalence of Wnt and R-spondin ligands during LGR5+ intestinal stem-cell self-renewal. Nature. 2017;545:238–242. doi: 10.1038/nature22313. PubMed DOI PMC

Janda C.Y., Dang L.T., You C., Chang J., de Lau W., Zhong Z.A., Yan K.S., Marecic O., Siepe D., Li X., et al. Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling. Nature. 2017;545:234–237. doi: 10.1038/nature22306. PubMed DOI PMC

Hsu P.J., Wu F.J., Kudo M., Hsiao C.L., Hsueh A.J., Luo C.W. A naturally occurring LGR4 splice variant encodes a soluble antagonist useful for demonstrating the gonadal roles of LGR4 in mammals. PLoS ONE. 2014;9:e106804. doi: 10.1371/journal.pone.0106804. PubMed DOI PMC

Hsu S.Y., Liang S.G., Hsueh A.J. Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol. Endocrinol. 1998;12:1830–1845. doi: 10.1210/mend.12.12.0211. PubMed DOI

McDonald T., Wang R., Bailey W., Xie G., Chen F., Caskey C.T., Liu Q. Identification and cloning of an orphan G protein-coupled receptor of the glycoprotein hormone receptor subfamily. Biochem. Biophys. Res. Commun. 1998;247:266–270. doi: 10.1006/bbrc.1998.8774. PubMed DOI

Barker N., Huch M., Kujala P., van de Wetering M., Snippert H.J., van Es J.H., Sato T., Stange D.E., Begthel H., van den Born M., et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6:25–36. doi: 10.1016/j.stem.2009.11.013. PubMed DOI

Jaks V., Barker N., Kasper M., van Es J.H., Snippert H.J., Clevers H., Toftgard R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat. Genet. 2008;40:1291–1299. doi: 10.1038/ng.239. PubMed DOI

Plaks V., Brenot A., Lawson D.A., Linnemann J.R., Van Kappel E.C., Wong K.C., de Sauvage F., Klein O.D., Werb Z. Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep. 2013;3:70–78. doi: 10.1016/j.celrep.2012.12.017. PubMed DOI PMC

de Visser K.E., Ciampricotti M., Michalak E.M., Tan D.W., Speksnijder E.N., Hau C.S., Clevers H., Barker N., Jonkers J. Developmental stage-specific contribution of LGR5+ cells to basal and luminal epithelial lineages in the postnatal mammary gland. J. Pathol. 2012;228:300–309. doi: 10.1002/path.4096. PubMed DOI

Yee K.K., Li Y., Redding K.M., Iwatsuki K., Margolskee R.F., Jiang P. Lgr5-EGFP marks taste bud stem/progenitor cells in posterior tongue. Stem Cells. 2013;31:992–1000. doi: 10.1002/stem.1338. PubMed DOI PMC

Barker N., Rookmaaker M.B., Kujala P., Ng A., Leushacke M., Snippert H., van de Wetering M., Tan S., Van Es J.H., Huch M., et al. Lgr5+ve stem/progenitor cells contribute to nephron formation during kidney development. Cell Rep. 2012;2:540–552. doi: 10.1016/j.celrep.2012.08.018. PubMed DOI

Morita H., Mazerbourg S., Bouley D.M., Luo C.W., Kawamura K., Kuwabara Y., Baribault H., Tian H., Hsueh A.J. Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol. Cell. Biol. 2004;24:9736–9743. doi: 10.1128/MCB.24.22.9736-9743.2004. PubMed DOI PMC

Snippert H.J., Haegebarth A., Kasper M., Jaks V., van Es J.H., Barker N., van de Wetering M., van den Born M., Begthel H., Vries R.G., et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010;327:1385–1389. doi: 10.1126/science.1184733. PubMed DOI

Leighton P.A., Mitchell K.J., Goodrich L.V., Lu X., Pinson K., Scherz P., Skarnes W.C., Tessier-Lavigne M. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature. 2001;410:174–179. doi: 10.1038/35065539. PubMed DOI

Mazerbourg S., Bouley D.M., Sudo S., Klein C.A., Zhang J.V., Kawamura K., Goodrich L.V., Rayburn H., Tessier-Lavigne M., Hsueh A.J. Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol. Endocrinol. 2004;18:2241–2254. doi: 10.1210/me.2004-0133. PubMed DOI

Pawaputanon Na Mahasarakham C., Ezura Y., Kawasaki M., Smriti A., Moriya S., Yamada T., Izu Y., Nifuji A., Nishimori K., Izumi Y., et al. BMP-2 enhances Lgr4 gene expression in osteoblastic cells. J. Cell. Physiol. 2016;231:887–895. doi: 10.1002/jcp.25180. PubMed DOI

Liu J., Wei W., Guo C.A., Han N., Pan J.F., Fei T., Yan Z.Q. Stat3 upregulates leucine-rich repeat-containing G protein-coupled receptor 4 expression in osteosarcoma cells. BioMed Res. Int. 2013;2013 doi: 10.1155/2013/310691. PubMed DOI PMC

Luo J., Zhou W., Zhou X., Li D., Weng J., Yi Z., Cho S.G., Li C., Yi T., Wu X., et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009;136:2747–2756. doi: 10.1242/dev.033571. PubMed DOI PMC

Ahmadzadeh A., Norozi F., Shahrabi S., Shahjahani M., Saki N. Wnt/beta-catenin signaling in bone marrow niche. Cell Tissue Res. 2016;363:321–335. doi: 10.1007/s00441-015-2300-y. PubMed DOI

Lacey D.L., Boyle W.J., Simonet W.S., Kostenuik P.J., Dougall W.C., Sullivan J.K., San Martin J., Dansey R. Bench to bedside: Elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat. Rev. Drug Discov. 2012;11:401–419. doi: 10.1038/nrd3705. PubMed DOI

Styrkarsdottir U., Thorleifsson G., Sulem P., Gudbjartsson D.F., Sigurdsson A., Jonasdottir A., Oddsson A., Helgason A., Magnusson O.T., Walters G.B., et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature. 2013;497:517–520. doi: 10.1038/nature12124. PubMed DOI

Zou Y., Ning T., Shi J., Chen M., Ding L., Huang Y., Kauderer S., Xu M., Cui B., Bi Y., et al. Association of a gain-of-function variant in LGR4 with central obesity. Obesity (Silver Spring) 2017;25:252–260. doi: 10.1002/oby.21704. PubMed DOI

Wang J., Liu R., Wang F., Hong J., Li X., Chen M., Ke Y., Zhang X., Ma Q., Wang R., et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat. Cell Biol. 2013;15:1455–1463. doi: 10.1038/ncb2867. PubMed DOI

Deng C., Reddy P., Cheng Y., Luo C.W., Hsiao C.L., Hsueh A.J. Multi-functional norrin is a ligand for the LGR4 receptor. J. Cell Sci. 2013;126:2060–2068. doi: 10.1242/jcs.123471. PubMed DOI PMC

Kim K.A., Zhao J., Andarmani S., Kakitani M., Oshima T., Binnerts M.E., Abo A., Tomizuka K., Funk W.D. R-spondin proteins: A novel link to beta-catenin activation. Cell Cycle. 2006;5:23–26. doi: 10.4161/cc.5.1.2305. PubMed DOI

Tomizuka K., Horikoshi K., Kitada R., Sugawara Y., Iba Y., Kojima A., Yoshitome A., Yamawaki K., Amagai M., Inoue A., et al. R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum. Mol. Genet. 2008;17:1278–1291. doi: 10.1093/hmg/ddn036. PubMed DOI

Yamada W., Nagao K., Horikoshi K., Fujikura A., Ikeda E., Inagaki Y., Kakitani M., Tomizuka K., Miyazaki H., Suda T., et al. Craniofacial malformation in R-spondin2 knockout mice. Biochem. Biophys. Res. Commun. 2009;381:453–458. doi: 10.1016/j.bbrc.2009.02.066. PubMed DOI

Aoki M., Mieda M., Ikeda T., Hamada Y., Nakamura H., Okamoto H. R-spondin3 is required for mouse placental development. Dev. Biol. 2007;301:218–226. doi: 10.1016/j.ydbio.2006.08.018. PubMed DOI

Kazanskaya O., Ohkawara B., Heroult M., Wu W., Maltry N., Augustin H.G., Niehrs C. The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. Development. 2008;135:3655–3664. doi: 10.1242/dev.027284. PubMed DOI

Bruchle N.O., Frank J., Frank V., Senderek J., Akar A., Koc E., Rigopoulos D., van Steensel M., Zerres K., Bergmann C. RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4. J. Investig. Dermatol. 2008;128:791–796. doi: 10.1038/sj.jid.5701088. PubMed DOI

Han T., Schatoff E.M., Murphy C., Zafra M.P., Wilkinson J.E., Elemento O., Dow L.E. R-spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nat. Commun. 2017;8:15945. doi: 10.1038/ncomms15945. PubMed DOI PMC

Seshagiri S., Stawiski E.W., Durinck S., Modrusan Z., Storm E.E., Conboy C.B., Chaudhuri S., Guan Y., Janakiraman V., Jaiswal B.S., et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660–664. doi: 10.1038/nature11282. PubMed DOI PMC

Jiang M.Y., Lee T.L., Hao S.S., Mahooti S., Baird S.M., Donoghue D.J., Haas M. Visualization of early prostatic adenocarcinoma as a stem cell disease. Oncotarget. 2016;7:76159–76168. doi: 10.18632/oncotarget.12709. PubMed DOI PMC

Merlos-Suarez A., Barriga F.M., Jung P., Iglesias M., Cespedes M.V., Rossell D., Sevillano M., Hernando-Momblona X., da Silva-Diz V., Munoz P., et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell. 2011;8:511–524. doi: 10.1016/j.stem.2011.02.020. PubMed DOI

Liang F., Yue J., Wang J., Zhang L., Fan R., Zhang H., Zhang Q. GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Med. Oncol. 2015;32:49. doi: 10.1007/s12032-015-0486-1. PubMed DOI

Pan D. The Hippo signaling pathway in development and cancer. Dev. Cell. 2010;19:491–505. doi: 10.1016/j.devcel.2010.09.011. PubMed DOI PMC

Harvey K.F., Hariharan I.K. The Hippo pathway. Cold Spring Harb. Perspect. Biol. 2012;4:a011288. doi: 10.1101/cshperspect.a011288. PubMed DOI PMC

Zeng Q., Hong W. The emerging role of the Hippo pathway in cell contact inhibition, organ size control and cancer development in mammals. Cancer Cell. 2008;13:188–192. doi: 10.1016/j.ccr.2008.02.011. PubMed DOI

Konsavage W.M., Jr., Yochum G.S. Intersection of Hippo/YAP and Wnt/beta-catenin signaling pathways. Acta Biochim. Biophys. Sin. (Shanghai) 2013;45:71–79. doi: 10.1093/abbs/gms084. PubMed DOI

Hao Y., Chun A., Cheung K., Rashidi B., Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J. Biol. Chem. 2008;283:5496–5509. doi: 10.1074/jbc.M709037200. PubMed DOI

Zhao B., Wei X., Li W., Udan R.S., Yang Q., Kim J., Xie J., Ikenoue T., Yu J., Li L., et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21:2747–2761. doi: 10.1101/gad.1602907. PubMed DOI PMC

Kanai F., Marignani P.A., Sarbassova D., Yagi R., Hall R.A., Donowitz M., Hisaminato A., Fujiwara T., Ito Y., Cantley L.C., et al. Taz: A novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 2000;19:6778–6791. doi: 10.1093/emboj/19.24.6778. PubMed DOI PMC

Zhao B., Li L., Tumaneng K., Wang C.Y., Guan K.L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP) Genes Dev. 2010;24:72–85. doi: 10.1101/gad.1843810. PubMed DOI PMC

Zhao B., Ye X., Yu J., Li L., Li W., Li S., Yu J., Lin J.D., Wang C.-Y., Chinnaiyan A.M., et al. Tead mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–1971. doi: 10.1101/gad.1664408. PubMed DOI PMC

Zaidi S.K., Sullivan A.J., Medina R., Ito Y., van Wijnen A.J., Stein J.L., Lian J.B., Stein G.S. Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J. 2004;23:790–799. doi: 10.1038/sj.emboj.7600073. PubMed DOI PMC

Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M., Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol. 2008;10:837–848. doi: 10.1038/ncb1748. PubMed DOI

Zanconato F., Forcato M., Battilana G., Azzolin L., Quaranta E., Bodega B., Rosato A., Bicciato S., Cordenonsi M., Piccolo S. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 2015;17:1218–1227. doi: 10.1038/ncb3216. PubMed DOI PMC

Kim M., Kim T., Johnson R.L., Lim D.S. Transcriptional co-repressor function of the Hippo pathway transducers YAP and TAZ. Cell Rep. 2015;11:270–282. doi: 10.1016/j.celrep.2015.03.015. PubMed DOI

Wang L., Shi S., Guo Z., Zhang X., Han S., Yang A., Wen W., Zhu Q. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS ONE. 2013;8:e65539. doi: 10.1371/journal.pone.0065539. PubMed DOI PMC

Zhou D., Zhang Y., Wu H., Barry E., Yin Y., Lawrence E., Dawson D., Willis J.E., Markowitz S.D., Camargo F.D., et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of yes-associated protein (Yap) overabundance. Proc. Natl. Acad. Sci. USA. 2011;108:E1312–E1320. doi: 10.1073/pnas.1110428108. PubMed DOI PMC

Varelas X., Miller B.W., Sopko R., Song S., Gregorieff A., Fellouse F.A., Sakuma R., Pawson T., Hunziker W., McNeill H., et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev. Cell. 2010;18:579–591. doi: 10.1016/j.devcel.2010.03.007. PubMed DOI

Barry E.R., Morikawa T., Butler B.L., Shrestha K., de la Rosa R., Yan K.S., Fuchs C.S., Magness S.T., Smits R., Ogino S., et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. 2013;493:106–110. doi: 10.1038/nature11693. PubMed DOI PMC

Imajo M., Miyatake K., Iimura A., Miyamoto A., Nishida E. A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling. EMBO J. 2012;31:1109–1122. doi: 10.1038/emboj.2011.487. PubMed DOI PMC

Cai J., Maitra A., Anders R.A., Taketo M.M., Pan D. Beta-catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev. 2015;29:1493–1506. doi: 10.1101/gad.264515.115. PubMed DOI PMC

Rosenbluh J., Nijhawan D., Cox A.G., Li X., Neal J.T., Schafer E.J., Zack T.I., Wang X., Tsherniak A., Schinzel A.C., et al. Beta-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell. 2012;151:1457–1473. doi: 10.1016/j.cell.2012.11.026. PubMed DOI PMC

Oudhoff M.J., Braam M.J.S., Freeman S.A., Wong D., Rattray D.G., Wang J., Antignano F., Snyder K., Refaeli I., Hughes M.R., et al. SETD7 controls intestinal regeneration and tumorigenesis by regulating Wnt/beta-catenin and Hippo/YAP signaling. Dev. Cell. 2016;37:47–57. doi: 10.1016/j.devcel.2016.03.002. PubMed DOI

Role of LGR5-positive mesenchymal cells in craniofacial development

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial-Mesenchymal Transition and Invasiveness

Extending the viability of human precision-cut intestinal slice model for drug metabolism studies

Human Colorectal Cancer from the Perspective of Mouse Models