Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 29, Pages 11851-11856Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1308362110
Keywords
-
Categories
Funding
- National Cancer Institute
- National Institutes of Health (NIH) [5R01GM098870-03, 5R01CA123238, CA100324, GM07739]
- Department of Defense Breast Cancer Research Program, Era of Hope Scholar Award [W871XWH-07-0372]
- NYSTEM [C024286]
- Waters Corporation
- New Jersey Cancer Commission SEED grant
- National Science Foundation (NSF) [CBET-0941143]
- Swedish Research Council
- Georg and Eva Klein Visiting Junior Scientist Award
- American Scandinavia Foundation
- Vinnova Marie Curie international qualification grant
- Deutsche Forschungsgemeinschaft (DFG) [Sta 1151/1-1]
Ask authors/readers for more resources
Peptidylarginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme that converts arginine and methylarginine residues to citrulline, with histone proteins being among its best-described substrates to date. However, the biological function of this posttranslational modification, either in histones or in nonhistone proteins, is poorly understood. Here, we show that PAD4 recognizes, binds, and citrullinates glycogen synthase kinase-3 beta (GSK3 beta), both in vitro and in vivo. Among other functions, GSK3 beta is a key regulator of transcription factors involved in tumor progression, and its dysregulation has been associated with progression of human cancers. We demonstrate that silencing of PAD4 in breast cancer cells leads to a striking reduction of nuclear GSK3 beta protein levels, increased TGF-beta signaling, induction of epithelial-to-mesenchymal transition, and production of more invasive tumors in xenograft assays. Moreover, in breast cancer patients, reduction of PAD4 and nuclear GSK3 beta is associated with increased tumor invasiveness. We propose that PAD4-mediated citrullination of GSK3 beta is a unique posttranslational modification that regulates its nuclear localization and thereby plays a critical role in maintaining an epithelial phenotype. We demonstrate a dynamic and previously unappreciated interplay between histone-modifying enzymes, citrullination of nonhistone proteins, and epithelial-to-mesenchymal transition.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available