Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance

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 m...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-12, Vol.108 (49), p.E1312-E1320
Main Authors: Zhou, Dawang, Zhang, Yongyou, Wu, Hongtan, Barry, Evan, Yin, Yi, Lawrence, Earl, Dawson, Dawn, Willis, Joseph E, Markowitz, Sanford D, Camargo, Fernando D, Avruch, Joseph
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
alleles
Animals
Biological Sciences
Blotting, Western
carcinogenesis
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
colon
Colon - metabolism
Colon - pathology
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
colorectal neoplasms
Drosophila
Female
Gene Expression Regulation, Neoplastic
HCT116 Cells
homeostasis
Humans
Immunohistochemistry
Insects
intestinal mucosa
Intestinal Mucosa - metabolism
Intestines - cytology
Male
Mice
Mice, Knockout
Mice, Transgenic
Phosphoproteins - genetics
Phosphoproteins - metabolism
Phosphorylation
PNAS Plus
Polypeptides
protein kinases
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
RNA Interference
Rodents
Stem cells
Stem Cells - cytology
Stem Cells - metabolism
Tissue Array Analysis
transcription (genetics)
Transcription Factors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1110428108