Keeping Stem Cells in Check: A Hippo Balancing Act
2013; Elsevier BV; Volume: 12; Issue: 1 Linguagem: Inglês
10.1016/j.stem.2012.12.004
ISSN1934-5909
Autores Tópico(s)Hippo pathway signaling and YAP/TAZ
ResumoKnowing when to stop proliferation is crucial for any regenerative process. In a recent issue of Nature, Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar report that the Hippo pathway component YAP negatively regulates Wnt signaling, thereby preventing stem cell overpopulation after a regenerative response in the intestine. Knowing when to stop proliferation is crucial for any regenerative process. In a recent issue of Nature, Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar report that the Hippo pathway component YAP negatively regulates Wnt signaling, thereby preventing stem cell overpopulation after a regenerative response in the intestine. During homeostasis a complex interplay of morphogenetic pathways preserve epithelial integrity in the gut. These pathways, which include Wnt and Notch signaling, maintain a functional stem cell pool and regulate differentiation processes. More recent data indicate that the same signaling cascades are crucial for proper tissue regeneration after injury of the adult intestine. For example, it has been demonstrated not only that Wnt signaling is critical for gut repair but also that artificial increase of Wnt activity, e.g., by infusion of the Wnt agonist R-spondin1, augments the efficacy of the regenerative response (Kim et al., 2005Kim K.A. Kakitani M. Zhao J. Oshima T. Tang T. Binnerts M. Liu Y. Boyle B. Park E. Emtage P. et al.Science. 2005; 309: 1256-1259Crossref PubMed Scopus (436) Google Scholar). In contrast to our rather extensive knowledge of pathways that regulate stem cell properties in the intestine during homeostasis and tissue regeneration, only a very limited number of studies examine the mechanisms that keep stem cells in check after a regenerative response to prevent tissue overcrowding and dysplasia. An important player in this so-called “crowd control” mechanism is the Hippo pathway. This pathway, originally discovered in Drosophila, is most well known for its ability to regulate organ size (reviewed in Mauviel et al., 2012Mauviel A. Nallet-Staub F. Varelas X. Oncogene. 2012; 31: 1743-1756Crossref PubMed Scopus (96) Google Scholar). When the Hippo cascade is active, the downstream effector of this pathway Yes-associated protein (YAP) is phosphorylated at S127 by the LATS1/2 kinases. Phosphorylated YAP remains in the cytoplasm and as such cannot exert its proproliferative and antiapoptotic function in the nucleus, which is mainly mediated by its binding to TEAD1-4 transcription factors. In addition, cytoplasmic YAP can directly antagonize the Wnt pathway, thereby further contributing to the role of Hippo signaling in preventing proliferation and stem cell expansion (Konsavage and Yochum, 2012Konsavage Jr., W.M. Yochum G.S. Acta Biochim Biophys Sin (Shanghai). 2012; (Published online September 30, 2012)https://doi.org/10.1093/abbs/gms084Crossref PubMed Scopus (54) Google Scholar). The relevance of the Wnt antagonizing effects of YAP in controlling intestinal stem cell expansion after regeneration was recently uncovered in an elegant series of experiments performed in the Camargo laboratory (Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar). Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar report that epithelial-specific overexpression of the YAP(S127A) mutant, which importantly is predominantly localized in the cytoplasm in this tissue, induces intestinal hypotrophy and loss of crypt base columnar stem cells. Mechanistically, YAP(S127A) expression results in abrogation of Wnt signaling in the intestine in vivo. In agreement with previous reports, YAP loss in the intestine only marginally affects intestinal homeostasis (Cai et al., 2010Cai J. Zhang N. Zheng Y. de Wilde R.F. Maitra A. Pan D. Genes Dev. 2010; 24: 2383-2388Crossref PubMed Scopus (370) Google Scholar); however, the effects of YAP loss become significant when a Wnt-dependent regenerative response is induced either by γ-irradiation or by adenovirus-mediated R-spondin1 expression. In those cases, YAP loss results in a rapid expansion of the intestinal stem cell compartment and formation of ectopic crypt regions and even microadenomas, which is in fact a phenotype very reminiscent of intestinal APC loss as observed in the APCmin mouse model. These data indicate that YAP is involved in controlling the activity of the Wnt pathway during regeneration and thereby also preventing tissue hypertrophy and dysplasia. The precise mechanism by which this occurs is not entirely resolved yet, although it is suggested by Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar that it does not involve sequestering of β-catenin in the cytoplasm or inhibition of GSK3β function within the β-catenin degradation complex, which are two previously reported mechanisms by which cytosolic YAP negatively regulates Wnt signaling (Konsavage and Yochum, 2012Konsavage Jr., W.M. Yochum G.S. Acta Biochim Biophys Sin (Shanghai). 2012; (Published online September 30, 2012)https://doi.org/10.1093/abbs/gms084Crossref PubMed Scopus (54) Google Scholar). Instead, Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar propose a novel mechanism in which cytoplasmic YAP directly inhibits nuclear translocation of Dishevelled proteins where it promotes Wnt target gene expression, in a parallel manner to the canonical β-catenin mediated activity of this pathway (Figure 1). In many respects, cancer can be perceived as a disease in which stem cell proliferation is no longer restricted and causes tissue overpopulation. This is often a consequence of mutations causing activation of pathways promoting stem cell proliferation and self-renewal. A prime example of this notion is the constitutive activation of the Wnt pathway seen in the vast majority of colorectal cancers (CRCs). Consequently, the Wnt target gene YAP is upregulated in many CRCs. Interestingly, Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar now identify a small fraction of CRCs that show low expression of YAP protein and that have a dismal prognosis. The mechanism by which YAP expression is restricted in these patients is unclear, but it could involve promoter methylation that is also described to be responsible for decreased expression of other negative regulators of the Wnt pathway. It should be noted that several of the findings by Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar contrast with previous paradigms of YAP function that were established in the field. First of all, the effects of epithelial cell-specific YAP overexpression in the intestine are opposite to the effects of YAP overexpression in the skin where it strongly promotes stem cell expansion and results in thickening of the skin (Schlegelmilch et al., 2011Schlegelmilch K. Mohseni M. Kirak O. Pruszak J. Rodriguez J.R. Zhou D. Kreger B.T. Vasioukhin V. Avruch J. Brummelkamp T.R. Camargo F.D. Cell. 2011; 144: 782-795Abstract Full Text Full Text PDF PubMed Scopus (772) Google Scholar). There are several possibilities for this contrasting phenotype including context-dependent pathway interactions, differential roles of the Wnt pathway in either tissue, or subcellular localization differences of the YAP(S127A) mutant. While the biological differences underlying the discrepancy between the effects of YAP expression in the skin and the intestine are not yet entirely clear, in the gut itself the effects of YAP overexpression are not unambiguous either. In the current study by Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar, epithelial cell-specific YAP(S127A) expression results in a degenerative phenotype; however, when the same YAP mutant is expressed using a ubiquitous promoter, intestinal dysplasia with expansion of undifferentiated progenitor cells is observed (Camargo et al., 2007Camargo F.D. Gokhale S. Johnnidis J.B. Fu D. Bell G.W. Jaenisch R. Brummelkamp T.R. Curr. Biol. 2007; 17: 2054-2060Abstract Full Text Full Text PDF PubMed Scopus (936) Google Scholar). These results are especially intriguing as it indicates that the Hippo pathway mediates potent paracrine effects of the intestinal stroma, a concept that is in line with a recent study reporting that YAP expression indeed has paracrine functions and promotes secretion of the EGFR ligand amphiregulin (Zhang et al., 2009Zhang J. Ji J.Y. Yu M. Overholtzer M. Smolen G.A. Wang R. Brugge J.S. Dyson N.J. Haber D.A. Nat. Cell Biol. 2009; 11: 1444-1450Crossref PubMed Scopus (318) Google Scholar). To conclude, the current work suggests that YAP is a tumor suppressor gene in CRC, as Barry et al., 2012Barry 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.Nature. 2012; (Published online November 25, 2012)https://doi.org/10.1038/nature11693Crossref Scopus (399) Google Scholar additionally showed that patients with low YAP expression levels have a poor prognosis and overexpression of YAP results in impaired subcutaneous tumor growth of the DLD-1 CRC cell line. Intriguingly, these findings appear to be counterintuitive based on previous work. Two recent reports showed that shRNA-mediated downregulation of YAP in a panel of CRC cell lines inhibits colony formation and subcutaneous tumor growth (Konsavage et al., 2012Konsavage Jr., W.M. Kyler S.L. Rennoll S.A. Jin G. Yochum G.S. J. Biol. Chem. 2012; 287: 11730-11739Crossref PubMed Scopus (205) Google Scholar; Zhou et al., 2011Zhou D. Zhang Y. Wu H. Barry E. Yin Y. Lawrence E. Dawson D. Willis J.E. Markowitz S.D. Camargo F.D. Avruch J. Proc. Natl. Acad. Sci. USA. 2011; 108: E1312-E1320Crossref PubMed Scopus (354) Google Scholar), which would be inconsistent with a tumor suppressor role for YAP in the intestine. One possibility for resolving these opposing findings can be reached by appreciating the different functions YAP has depending on its subcellular localization. In this respect, nuclear YAP is thought to function mainly as an oncogene and promotes proliferation and expression of antiapoptotic proteins, while cytoplasmic YAP is a typical tumor suppressor that downregulates the Wnt pathway. If this hypothesis is true, it will be a true challenge to appropriately target this molecule for clinical benefit. Clever strategies need to be developed that selectively inhibit the oncogenic properties of this protein while promoting the tumor suppressor functions. Potentially, this could be achieved by interfering with the YAP-TEAD interaction or by inhibiting its nuclear translocation. In any case, it will be interesting to follow how efforts to manipulate YAP function will develop.
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