Zhou D, Zhang Y, Wu H 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 108:E1312-20

Department of Molecular Biology, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2011; 108(49):E1312-20. DOI: 10.1073/pnas.1110428108
Source: PubMed


Ablation of the kinases Mst1 and Mst2, orthologs of the Drosophila antiproliferative kinase Hippo, from mouse intestinal epithelium caused marked expansion of an undifferentiated stem cell compartment and loss of secretory cells throughout the small and large intestine. Although median survival of mice lacking intestinal Mst1/Mst2 is 13 wk, adenomas of the distal colon are common by this age. Diminished phosphorylation, enhanced abundance, and nuclear localization of the transcriptional coactivator Yes-associated protein 1 (Yap1) is evident in Mst1/Mst2-deficient intestinal epithelium, as is strong activation of β-catenin and Notch signaling. Although biallelic deletion of Yap1 from intestinal epithelium has little effect on intestinal development, inactivation of a single Yap1 allele reduces Yap1 polypeptide abundance to nearly wild-type levels and, despite the continued Yap hypophosphorylation and preferential nuclear localization, normalizes epithelial structure. Thus, supraphysiologic Yap polypeptide levels are necessary to drive intestinal stem cell proliferation. Yap is overexpressed in 68 of 71 human colon cancers and in at least 30 of 36 colon cancer-derived cell lines. In colon-derived cell lines where Yap is overabundant, its depletion strongly reduces β-catenin and Notch signaling and inhibits proliferation and survival. These findings demonstrate that Mst1 and Mst2 actively suppress Yap1 abundance and action in normal intestinal epithelium, an antiproliferative function that frequently is overcome in colon cancer through Yap1 polypeptide overabundance. The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target.

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Available from: Dawn Dawson, Sep 01, 2015
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    • "However, in this case it is the SWH activity that is involved in promoting the expression of Notch targets [49], [50]. In other contexts, such as the mouse intestine, accumulation of Yap1, the mouse Yki homolog, and therefore inhibition of the SWH promotes Notch activity [51], [52]. These examples demonstrate that the interactions between Notch and the SWH are highly dependent on cellular context. "
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    ABSTRACT: During development, tissues and organs must coordinate growth and patterning so they reach the right size and shape. During larval stages, a dramatic increase in size and cell number of Drosophila wing imaginal discs is controlled by the action of several signaling pathways. Complex cross-talk between these pathways also pattern these discs to specify different regions with different fates and growth potentials. We show that the Notch signaling pathway is both required and sufficient to inhibit the activity of Yorkie (Yki), the Salvador/Warts/Hippo (SWH) pathway terminal transcription activator, but only in the central regions of the wing disc, where the TEAD factor and Yki partner Scalloped (Sd) is expressed. We show that this cross-talk between the Notch and SWH pathways is mediated, at least in part, by the Notch target and Sd partner Vestigial (Vg). We propose that, by altering the ratios between Yki, Sd and Vg, Notch pathway activation restricts the effects of Yki mediated transcription, therefore contributing to define a zone of low proliferation in the central wing discs.
    PLoS ONE 08/2014; 9(8):e106211. DOI:10.1371/journal.pone.0106211 · 3.23 Impact Factor
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    • "Using immunohistochemistry, YAP has been found to be either strongly expressed or highly localized to the nucleus (where it is active in gene transcription) in human cancers compared with normal tissue. Increased expression and/or nuclear accumulation of YAP has been reported in a wide array of human cancers including HCC, prostate cancer, colorectal carcinoma (CRC), NSCLC, ovarian cancer, ccRCC, pancreatic carcinoma, esophageal squamous cell carcinoma, urothelial carcinoma of the bladder, and skin basal cell carcinoma (Additional file 1: Table S1) [34,61-63,67,71,72,76,83-87]. Notably, expression or nuclear localization of YAP is associated with poorer tumor differentiation and higher-grade tumors [76,86]. "
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    ABSTRACT: Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention.
    Clinical and Translational Medicine 07/2014; 3(1):25. DOI:10.1186/2001-1326-3-25
    • "Camargo et al., observed in their study that YAP could restrict the differentiation of stem cell in the intestine and expand multipotent undifferentiated progenitor cells.[16] Zhou et al., study confirms that overexpression of YAP promotes colonic tumorigenesis through inducing the ablation of kinases MST1 and MST2.[17] TAZ plays a similar function in cell proliferation and tumorigenesis. "
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    ABSTRACT: Background/Aims: Hippo pathway plays a crucial role in cell proliferation, apoptosis, and tumorigenesis. This study aimed to investigate the expression of Hippo pathway components in the progression and metastasis of colorectal cancer (CRC). Materials and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the mRNA expression levels of MST1, LATS2, YAP, TAZ, TEAD1, CDX2, and OCT4, and western blot (WB) was used to examine the protein expression levels of MST1, YAP, TEAD1, and CDX2 in 30 specimens of human colorectal adenomas, 50 pairs of human CRC tissues, and adjacent nontumorous tissues from CRC patients. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as the housekeeping gene in qRT-PCR. Results: The mRNA expression levels of MST1 and LATS2 showed an increasing tendency from CRC to adjacent nontumorous tissues (P < 0.001). Conversely, the mRNA expression levels of YAP, TAZ, TEAD, and OCT4 showed a decreasing tendency from CRC to adjacent nontumorous tissues (P < 0.001). MST1 protein was downregulated and YAP and TEAD1 proteins were upregulated in CRC (all P < 0.001). The mRNA and protein expression levels of CDX2 in CRC were significantly lower than those in colorectal adenomas and adjacent nontumorous tissues (P < 0.001), but there was no significant difference between the latter two groups (qRT-PCR, P = 0.113; WB, P = 0.151). Furthermore, statistical analysis showed that the expression levels of Hippo signal pathway components were associated with tumor differentiation, lymph node metastasis, and TNM stage. Conclusion: Hippo pathway is suppressed in the progression from colorectal adenomas to CRC and is associated with CRC progression and metastasis. This study suggests the components of Hippo pathway might be prognostic indicators for CRC patients.
    Saudi Journal of Gastroenterology 05/2014; 20(3):188-94. DOI:10.4103/1319-3767.133025 · 1.12 Impact Factor
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