title: β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.
abstract: 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 β-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 β-catenin destruction complex.
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.affiliation: Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030;
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo, Kyoto 606-8501, Japan.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000236:Adenoma / Q000201:enzymology / Q000503:physiopathology; D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D000090683:Hippo Signaling Pathway; D006801:Humans; D007422:Intestines / Q000503:physiopathology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases
keywords: APC; Hippo signaling; TAZ; YAP; tumorigenesis; β-catenin