β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis

被引:152
作者
Cai, Jing [1 ,2 ]
Maitra, Anirban [3 ]
Anders, Robert A. [4 ]
Taketo, Makoto M. [5 ]
Pan, Duojia [1 ,2 ]
机构
[1] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA
[3] Univ Texas MD Anderson Canc Ctr, Sheikh Ahmed Bin Zayed Al Nahyan Ctr Pancreat Can, Houston, TX 77030 USA
[4] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
[5] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan
关键词
beta-catenin; APC; Hippo signaling; TAZ; YAP; tumorigenesis; YES-ASSOCIATED PROTEIN; ADENOMATOUS POLYPOSIS; GENE-EXPRESSION; COLON-CANCER; SIZE-CONTROL; STEM-CELLS; PATHWAY; MUTATION; INACTIVATION; ONCOPROTEIN;
D O I
10.1101/gad.264515.115
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the beta-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo-YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the beta-catenin destruction complex.
引用
收藏
页码:1493 / 1506
页数:14
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