Dataset Information

Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function.

ABSTRACT: Conventional wisdom holds that methylation of RTKs should be restricted to intracellular sites. Alterations--such as deletion, mutation, and proteolytic cleavage events--to the extracellular ligand binding and dimer interface domains of the EGFR can induce EGFR dimer formation, leading to aberrant receptor activation and oncogenic activity. Recently, the extracellular domain of EGFR was also shown to be methylated, suggesting that posttranslational protein methylation events directed to the extracellular dimer interface provide another mechanism to regulate the EGFR activation state by modulating receptor dimerization. Critically, these methylation events abrogate response to conformation-specific therapeutic antibodies such as cetuximab. In this issue of the JCI, Liao et al. investigate the role of protein arginine methyltransferase I (PRMT1) in regulating EGFR function in colorectal cancer. The authors provide evidence that methylation of R198 and R200 within the dimer interface enhances growth factor ligand binding and cetuximab resistance through induction and stabilization of the active EGFR dimer conformation. Delineation of these and other subtleties involved in oncogenic RTK activation and their response to targeted therapies should facilitate the development of improved antibody-based treatments.

SUBMITTER: Epstein DM

PROVIDER: S-EPMC4665791 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function.

Epstein David M DM Buck Elizabeth E

The Journal of clinical investigation 20151116 12

Conventional wisdom holds that methylation of RTKs should be restricted to intracellular sites. Alterations--such as deletion, mutation, and proteolytic cleavage events--to the extracellular ligand binding and dimer interface domains of the EGFR can induce EGFR dimer formation, leading to aberrant receptor activation and oncogenic activity. Recently, the extracellular domain of EGFR was also shown to be methylated, suggesting that posttranslational protein methylation events directed to the extr ...[more]

PMID: 26571394

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Project description:High throughput screening (HTS) is an important component of lead discovery, with virtual screening playing an increasingly important role. Both methods typically suffer from lack of sensitivity and specificity against their true biological targets. With ever-increasing screening libraries and virtual compound collections, it is now feasible to conduct follow-up experimental testing on only a small fraction of hits. In this context, advances in virtual screening that achieve enrichment of true actives among top-ranked compounds ("early recognition") and, hence, reduce the number of hits to test, are highly desirable. The standard ligand-based virtual screening method for large compound libraries uses a molecular similarity search method that ranks the likelihood of a compound to be active against a drug target by its highest Tanimoto similarity to known active compounds. This approach assumes that the distributions of Tanimoto similarity values to all active compounds are identical (i.e., same mean and standard deviation)-an assumption shown to be invalid (Baldi and Nasr, 2010). Here, we introduce two methods that improve early recognition of actives by exploiting similarity information of all molecules. The first method ranks a compound by its highest z-score instead of its highest Tanimoto similarity, and the second by an aggregated score calculated from its Tanimoto similarity values to all known actives and inactives (or a large number of structurally diverse molecules when information on inactives is unavailable). Our evaluations, which use datasets of over 20 HTS campaigns downloaded from PubChem, indicate that compared to the conventional approach, both methods achieve a ~10% higher Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC) score-a metric of early recognition. Given the increasing use of virtual screening in early lead discovery, these methods provide straightforward means to enhance early recognition.

Dataset Information

Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function.

Publications

Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function.

Similar Datasets

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