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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Birtley JR,Alomary M,Zanini E,Antony J,Maben Z,Weaver GC,Von Arx C,Mura M,Marinho AT,Lu H,Morecroft EVN,Karali E,Chayen NE,Tate EW,Jurewicz M,Stern LJ,Recchi C,Gabra H

doi

10.1038/s41467-019-10966-8

subject

Has Abstract

pub_date

2019-07-17 00:00:00

pages

3134

issue

1

issn

2041-1723

pii

10.1038/s41467-019-10966-8

journal_volume

10

pub_type

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