Related Experiment Video
Updated: Oct 9, 2025
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in
Eunna Huh1, Jonathan Gallion2,3, Melina A Agosto4,5
1Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030.
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.
Insights
Somatic mutations in cancer frequently target specific positions across multiple G protein-coupled receptors (GPCRs), not just single genes. These recurrent mutations perturb GPCR signaling, potentially driving tumor growth and survival.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- G protein-coupled receptors (GPCRs) represent the largest human protein family, crucial in cellular signaling.
- GPCRs modulate cancer mechanisms through downstream pathways involving G proteins, arrestins, and effectors.
- The vast number of GPCRs suggests that mutations in different receptors could converge on similar oncogenic signaling.
Purpose of the Study:
- To investigate if somatic mutations in cancer are enriched across multiple GPCRs at functionally similar positions.
- To determine if specific GPCR positions are recurrently mutated in cancer, affecting receptor function.
- To explore the potential of GPCRs as oncogenic drivers or enablers through mutated cognate positions.
Main Methods:
- Systematic aggregation of somatic cancer mutations across Class A GPCRs.
- Analysis of mutation distribution to identify nonrandom patterns at specific amino acid positions.
- Phenotypic characterization of mutated GPCRs to assess effects on G protein activation and beta-arrestin recruitment.
Main Results:
- A nonrandom distribution of somatic mutations was observed across Class A GPCRs.
- Specific cognate positions within functional motifs were enriched for impactful, recurrent mutations in individual cancer types.
- No single GPCR gene was solely responsible; multiple receptors showed substitutions at a few shared positions.
- Mutations were found to perturb G protein activation and/or beta-arrestin recruitment.
Conclusions:
- Recurrent oncogenic mutations can affect multiple GPCRs at cognate positions to subvert signaling pathways.
- These mutated GPCRs may act as drivers or enablers of tumor growth and survival.
- Targeting these mutated GPCRs offers potential new therapeutic strategies in oncology.
More Related Videos
08:04Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
12:49Mutagenesis and Analysis of Genetic Mutations in the GC-rich KISS1 Receptor Sequence Identified in Humans with Reproductive Disorders
Published on: September 4, 2011
Related Concept Videos
01:15G Protein-coupled Receptors
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
01:30Transducer Mechanism: G Protein–Coupled Receptors
GPCRs are also called heptahelical,...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:38The Ras Gene
Ras is a...
01:21G-protein Coupled Receptors