Publication Date

12-21-2021

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2113373118

PMID

34916293

PMCID

PMC8713800

PubMedCentral® Posted Date

12-16-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Calcium, Cell Line, Tumor, Computer Simulation, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Neoplastic, Humans, Mutation, Neoplasms, Protein Conformation, Receptors, G-Protein-Coupled, beta-Arrestins, G protein-coupled receptor (GPCR), cancer, evolutionary action (EA), mutational signatures, β-arrestin

Abstract

G protein-coupled receptors (GPCRs) are the largest family of human proteins. They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and effectors, activate downstream pathways that often modulate hallmark mechanisms of cancer. Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling similarly so as to favor a tumor. We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR function are distributed across many receptors. To test this possibility, we systematically aggregated somatic cancer mutations across class A GPCRs and found a nonrandom distribution of positions with variant amino acid residues. Individual cancer types were enriched for highly impactful, recurrent mutations at selected cognate positions of known functional motifs. We also discovered that no single receptor drives this pattern, but rather multiple receptors contain amino acid substitutions at a few cognate positions. Phenotypic characterization suggests these mutations induce perturbation of G protein activation and/or β-arrestin recruitment. These data suggest that recurrent impactful oncogenic mutations perturb different GPCRs to subvert signaling and promote tumor growth or survival. The possibility that multiple different GPCRs could moonlight as drivers or enablers of a given cancer through mutations located at cognate positions across GPCR paralogs opens a window into cancer mechanisms and potential approaches to therapeutics.

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