title: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Epstein
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buck
mesh_terms: D000818:Animals; D000068818:Cetuximab / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D012097:Repressor Proteins; D011484:Protein-Arginine N-Methyltransferases; D066246:ErbB Receptors; D000068818:Cetuximab