EGFR protein editing by serine hydroxymethyl transferase SHMT2

Abstract The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, relies on phosphorylation for signal transduction1,2. It is known that the EGFR gene often harbors activating mutations for protein sequence change, leading to constitutive phosphorylation and activation of the EGFR protein in various cancers3. This study reveals that EGFR proteins, isolated from lung cancer tissues or cell lines, possess multiple glycine-to-serine (G>S) protein sequence modifications, which are not associated with EGFR gene mutations. These EGFR proteins enlist Serine Hydroxymethyl Transferase 2 (SHMT2) to induce glycine hydroxymethylation, resulting in G>S/GS>SG protein sequence editing. SHMT2 catalyzes the protein editing predominantly within the GS-islands of the EGFR protein, utilizing either free serine amino acids present within cells or the serine residue adjacent to glycine residue as the hydroxymethyl group donor. The G>S/GS>SG editing within GS islands G719S720, G810S811, and G1103S1104 causes significantly amplify of EGFR signaling activity, stimulates cancer cell growth, and induces drug resistance. In lung cancer cells, depletion of SHMT2 or inhibition with SHIN1 suppresses glycine hydroxymethylation, eliminating EGFR protein G>S/GS>SG editing and reducing resistance to EGFR-targeting drugs. Our findings not only identify a novel form of protein mutation through directly editing, but also underscore the importance of protein editing driving EGFR activation, thereby presenting potential avenues for EGFR-targeted therapy.