Scientists Identified a New Role for EGFR
Protein encoded by epidermal growth factor receptor (EGFR) gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Mutations in this gene are associated with lung cancer. Multiple alternatively spliced transcript variants that encode different protein isoforms have been found for this gene.
Recently scientists found that under conditions of oxygen starvation often encountered by tumors, the EGFR gums up the cell's miRNA-processing machinery. EGFR signals to a key protein in miRNA processing was argonaute 2, or AGO2.
The new finding points to a potential new prognostic marker for breast cancer, also provides the first evidence of a growth factor signaling pathway regulating miRNA maturation. The study showed how signal communicate with miRNA.
The scientists established the relationship in cell line experiments, confirmed it in a mouse model and human breast cancer samples. Low-oxygen conditions cause EGFR overexpression. There is signal induction inside of a cell, in this case through EGFR, a protein complex that processes precursors into mature miRNA to perform a function. EGFR penetrates the cell membrane to receive signals from growth factors outside of the cell. After a growth factor binds to it, EGFR conveys the signal into the cell by attaching phosphate groups to other proteins, often acting as a molecular "on switch." Anti-angiogenesis drugs designed to kill tumors by blocking their ability to spin webs of supportive blood vessels often succeed at first, but then fail against the more malignant cells that survive hypoxia. When hypoxia hits, EGFR gets active and gets eaten.
EGFR attaches phosphate groups to AGO2, which in turn weakens AGO2's ability to connect with Dicer to produce mature microRNAs. EGFR's effect is stronger during oxygen starvation than under normal conditions. The miRNAs regulated by phosphorylated AGO2, including miR-31, miR-192 and miR-193a-5p, also shared a long-loop structure in their precursors that miRNAs unaffected by AGO2 phosphorylation lack. EGFR-mediated AGO2 phosphorylation blocks cell death and enhances invasiveness under hypoxia.
They did an experiment on mouse model of breast cancer finding that expression of EGFR and the presence of phosphorylated AGO2 increase during tumor progression under oxygen-starved conditions.
The study also expands people’s insight into other receptors that regulate miRNAs.
Article Link: Scientists Identified a New Role for EGFRTags: EGFR, AGO2, Protein Kinase