UMMS Affiliation
Department of Pathology; Graduate School of Biomedical Sciences
Publication Date
2019-07-17
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Enzymes and Coenzymes | Genetic Phenomena | Neoplasms | Structural Biology
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 A 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.
Keywords
Cell invasion, Growth factor signalling, Ovarian cancer, Tumour-suppressor proteins, X-ray crystallography
Rights and Permissions
Copyright © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
10.1038/s41467-019-10966-8
Source
Nat Commun. 2019 Jul 17;10(1):3134. doi: 10.1038/s41467-019-10966-8. Link to article on publisher's site
Journal/Book/Conference Title
Nature communications
Related Resources
PubMed ID
31316070
Repository Citation
Birtley, James R.; Maben, Zachary; Weaver, Grant C.; Jurewicz, Mollie M.; Stern, Lawrence J.; Recchi, Chiara; and Gabra, Hani, "Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions" (2019). Open Access Articles. 3927.
https://escholarship.umassmed.edu/oapubs/3927
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Cancer Biology Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Neoplasms Commons, Structural Biology Commons
Comments
Full author list omitted for brevity. For the full list of authors, see article.