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Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions

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Title: Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions
Authors: Birtley, JR
Alomary, M
Zanini, E
Antony, J
Maben, Z
Weaver, G
Von Arx, C
Mura, M
Marinho, AT
Lu, H
Morecroft, E
Karali, E
Chayen, N
Tate, E
Jurewicz, M
Stern, L
Recchi, C
Gabra, H
Item Type: Journal 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.
Issue Date: 17-Jul-2019
Date of Acceptance: 6-Jun-2019
URI: http://hdl.handle.net/10044/1/71553
DOI: https://dx.doi.org/10.1038/s41467-019-10966-8
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 10
Copyright Statement: © 2019 The Author(s). 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/.
Sponsor/Funder: Ovarian Cancer Action
Funder's Grant Number: N/A
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
NEURITE OUTGROWTH
OVARIAN-CANCER
METHYLATION
EXPRESSION
PROTEIN
GENE
INTERFACE
BIOMARKER
PROMOTER
DIGLONS
MD Multidisciplinary
Publication Status: Published
Article Number: 3134
Appears in Collections:Department of Surgery and Cancer
Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences