Editors' ChoiceCancer

Twofold tumor suppression

Sci. Signal.  04 Aug 2015:
Vol. 8, Issue 388, pp. ec214
DOI: 10.1126/scisignal.aad1339

Adenomatous polyposis coli (APC) is a tumor suppressor that prevents the expression of growth-promoting genes by antagonizing Wnt signaling. In this context, APC acts as a scaffold in a mutiprotein complex that promotes degradation of the transcription factor β-catenin in the absence of the ligand Wnt. Heterozygosity for inactivating mutations in APC cause the formation of spontaneous intestinal tumors in mice and cause FAP (familial adenomatous polyposis), an inherited syndrome characterized by the formation of numerous colorectal polyps, in humans. Cai et al. found that APC mutations also contributed to intestinal tumorigenesis by reducing Hippo signaling, a kinase cascade that suppresses cell growth by inducing the phosphorylation, cytoplasmic retention, and degradation of the transcriptional coactivators YAP and TAZ. Compared to normal neighboring tissue, adenomas from APC+/- mice and adenomas from FAP patients both showed increased nuclear accumulation of YAP. The total abundance of YAP was greater in lysates from mouse adenomas compared to normal tissue, and the amount of phosphorylated YAP was reduced in neoplastic tissue. Experiments in APC+/- mice and in cultured HEK293 cells indicated that APC promoted activation of the Hippo core kinase Lats1 downstream of the kinase Mst1 (also known as Hippo). APC coimmunoprecipitated with Lats1 and the Mst1 binding partner Sav1, suggesting that APC acts as a scaffold protein for the kinases of the Hippo pathway. APC's role in the Wnt–β-catenin pathway and the Hippo pathway appeared independent. because Wnt stimulation, which triggers dissociation of the β-catenin destruction complex, did not promote nuclear localization of YAP or expression of a YAP reporter gene in HEK293 cells. The β-catenin destruction complex does not form in the absence of β-catenin, but there was no change in the abundance or subcellular localization of YAP or TAZ in colonic epithelia lacking β-catenin. Conversely, the absence of YAP and TAZ in the colonic epithelium did not affect the abundance or subcellular localization of β-catenin. However, the stabilization and nuclear accumulation of both β-catenin and YAP contributed to APC+/- intestinal phenotypes. Mice lacking Sav1 in the intestinal epithelium did not exhibit altered intestinal morphology or develop polyps, but loss of Sav1 enhanced the intestinal phenotypes of mice overexpressing β-catenin in the intestinal epithelium and promoted the development of adenomatous polyps, effectively mimicking APC+/- phenotypes. Knocking out YAP had no effect on intestinal development or morphology, but prevented the formation of intestinal adenomas in APC+/- mice. These findings indicate that APC has independent scaffolding functions in the Hippo and Wnt–β-catenin pathways. APC limits cell proliferation and tumor formation in the intestine by both promoting Hippo signaling and antagonizing Wnt–β-catenin signaling.

J. Cai, A. Maitra, R. A. Anders, M. M. Taketo, D. Pan, β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis. Genes Dev. 29, 1493–1506 (2015). [PubMed]

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