Department of Pathology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Enzymes and Coenzymes | Genetic Phenomena | Neoplasms | Structural Biology
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.
Cell invasion, Growth factor signalling, Ovarian cancer, Tumour-suppressor proteins, X-ray crystallography
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DOI of Published Version
Nat Commun. 2019 Jul 17;10(1):3134. doi: 10.1038/s41467-019-10966-8. Link to article on publisher's site
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.
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This work is licensed under a Creative Commons Attribution 4.0 License.