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PMID: 21610251 Published · epublish English Journal Article

α-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1.

Science signaling ·Vol. 4 ·No. 174 ·2011-05-24 ·Pages ra33

Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, Lantz DM, Seykora JT, Vasioukhin V

Abstract

The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of αE (α epithelial) catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of αE-catenin and the tumor suppressor-encoding gene p53. A small interfering RNA screen revealed a functional connection between αE-catenin and Yap1. By interacting with Yap1, αE-catenin promoted its cytoplasmic localization, and Yap1 showed constitutive nuclear localization in αE-catenin-null cells. We also found an inverse correlation between αE-catenin abundance and Yap1 activation in human squamous cell carcinoma tumors. These findings identify αE-catenin as a tumor suppressor that inhibits Yap1 activity and sequesters it in the cytoplasm.

MeSH Terms
Active Transport, Cell Nucleus/genetics Adaptor Proteins, Signal Transducing/genetics,metabolism Animals Carcinoma, Squamous Cell/genetics,metabolism,pathology Cell Cycle Proteins Cell Line, Tumor Cell Nucleus/genetics,metabolism Cell Proliferation HEK293 Cells Humans Mice Mice, Nude Mice, Transgenic Phosphoproteins/genetics,metabolism Transcription Factors Tumor Suppressor Protein p53/genetics,metabolism YAP-Signaling Proteins alpha Catenin/genetics,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Cell Cycle Proteins Phosphoproteins TP53 protein, human Transcription Factors Tumor Suppressor Protein p53 YAP-Signaling Proteins YAP1 protein, human Yap1 protein, mouse alpha Catenin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Silvis Mark R
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Kreger Bridget T
Lien Wen-Hui
Klezovitch Olga
Rudakova G Marianna
Camargo Fernando D
Lantz Dan M
Seykora John T
Vasioukhin Valeri
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Article Info
Journal
Science signaling
Abbr.
Sci Signal
ISSN
1937-9145
DOI
10.1126/scisignal.2001823
Published
2011-05-24
Epub
2011-00-24
Pages
ra33
Language
English
Region
United States
NLM ID
101465400
PMCID
PMC3366274
Subset
IM
Grants
NIAMS NIH HHS · R01 AR051380 · United States
NCI NIH HHS · R01 CA098161 · United States
NCI NIH HHS · R01 CA131047 · United States
NCI NIH HHS · T32 CA009657 · United States
External Links
PubMed source DOI: 10.1126/scisignal.2001823 PMC Full Text View journal details
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