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

Abstract

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.

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

“…It is also possible that basal Myc activity plays a minor role in normal homeostasis of mammalian intestines, but its elevated activity is essential for abnormal proliferation due to oncogenic mutations or loss of APC. In this regard, Myc may resemble Yap, which appears to be dispensable for normal homeostasis of the intestine but is required for overproliferation of intestine cells induced by injury or oncogenic mutations [39,40]. It would be interesting to determine whether Myc is also regulated by Hpo signaling and plays a role in adult tissue regeneration in mammals.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Later evidence supports that in many tissues the Hippo pathway has a stronger impact on the tissue-specific stem cell compartment, possibly inhibiting their proliferation or self-renewal. It was first observed that intestinal-specific overexpression of YAP or knockout of Mst1/2 in mice caused marked expansion of the stem cell compartment (Camargo et al, 2007;Zhou et al, 2011a). Knockout of Hippo pathway components Mst1/2, Sav1, and Mer in liver also leads to accumulation of liver stem cells (Benhamouche et al, 2010;Lee et al, 2010;Lu et al, 2010;Song et al, 2010).…”

Wnt/β-Catenin Signaling Regulates Yes-associated Protein (YAP) Gene Expression in Colorectal Carcinoma Cells

“…In the mouse, YAP overexpression or conditional deletion of Mst1/2 leads to hepatomegaly (14 -16). Removal of Mst kinases in the mouse gastrointestinal tract leads to increased numbers of stem cells and proliferative transit amplifying cells and an impairment of epithelial cell differentiation (17). Moreover, the Hippo pathway is critical for establishment and maintenance of the intestinal crypt microenvironment and it is required for repair of the intestinal epithelium following injury (14,17,18).…”

“…Deregulation of Hippo/YAP signaling has been implicated in intestinal tumorigenesis (14,17,18). YAP expression is elevated in human primary colonic tumors compared with its expression in uninvolved tissue and YAP expression is increased in the intestinal tumors that arise in the adenomatous polyposis coli multiple intestinal neoplasia (APC min ) mouse (14,18,19).…”