An essential role of PRMT1-mediated EGFR methylation in EGFR activation by ribonuclease 5

[摘要] Methylation at Arg198 and Arg200 residues of the EGFR extracellular domain by PRMT1 have been demonstrated to enhance EGFR activation by the canonical ligands, EGF and TGFα. On the other hand, RNase 5 was identified as a new ligand of EGFR recently. However, the interplay between EGFR methylation and RNase 5 in EGFR activation is still unclear. Here, we showed that RNase 5 activated EGFR and enhanced cell proliferation in colorectal cancer cells. PRMT1 positively regulated EGFR signaling activation by RNase 5. Inhibition of EGFR methylation by methylation-site mutagenesis reduced the binding affinity of RNase 5 to EGFR and abrogated RNase 5-mediated EGFR activation, suggesting that PRMT1-mediated EGFR methylation is critical for EGFR activation by RNase 5. Notably, RNase 5 diminished the inhibitory activity of cetuximab on colorectal cancer cells, implying RNase 5 is a potential biomarker to predict cetuximab response in colorectal cancer.

[学科分类] 肿瘤学

[关键词] EGFR;arginine methylation;PRMT1;cetuximab;RNase;angiogenin