Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions
Year: 2019
Type: article
Abstract: OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 Å resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers.
Source: Nature Communications
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Energy, Eli Lilly and Company, Cancer Research UK, Ovarian Cancer Action, Imperial College London, King Abdulaziz City for Science and Technology, Universität Konstanz, National Institutes of Health, Office of Science, University of Massachusetts Medical School, Engineering and Physical Sciences Research Council, Fundação para a Ciência e a Tecnologia, National Institute of Allergy and Infectious Diseases, Argonne National Laboratory, Brookhaven National Laboratory
Awards: G102163711, G107546177, G1285306620, G1313983767, G1505794299, G1664757510, G171842289, G1868695577, G1887435909, G2101401529, G2287611682, G241279073, G262962599, G2887060908, G3075337988, G3262563802, G340565428, G357145406, G3850097093, Structure and Function of MHC Proteins, G4972998915, G498139845, G5106849484, G5417557083, G5535608740, G5633341255, G5765906131, G6733788163, G6848031779, G6918803902, G7368700025, G7463374569, Structure and Function of Class II MHC Proteins, Training in Immunology and Microbiology, EPSRC Centre for Doctoral Training in Physical Sciences Innovation in Chemical Biology for Bioindustry and Healthcare, Structure and Function of Class II MHC Proteins, G9000113341, G969889393, G993149817
OpenAlex ID: W2960723617