MIT chemists reported on Apr. 17 that changes in the composition of a cell's membrane can influence the activity of a key receptor involved in cancer proliferation. The study, published in eLife, found that increasing negatively charged lipids in the membrane can lock the epidermal growth factor receptor (EGFR) into an overactive state.
This research matters because EGFR plays a central role in controlling how cells grow and divide. Overactivity of this receptor is linked to several cancers, including lung cancer and glioblastoma, which often show higher levels of these negatively charged lipids.
Lead author Shwetha Srinivasan PhD '22 and colleagues discovered that when membranes contained up to 60 percent negatively charged lipids—compared to the normal 15 percent—the EGFR was stuck in its active form. "If the membrane has high levels of negatively charged lipids, then it's always in that open conformation. It doesn't matter if ligand is bound or unbound," said Srinivasan. "It's always in the conformation that's telling the cell to grow, not just when EGF binds." This could help explain why some cancer cells divide uncontrollably.
The team used nanodiscs—synthetic membranes with embedded receptors—to mimic real cell membranes and single molecule FRET technology to observe how EGFR shape changes under different conditions. Previous work by co-authors Gabriela Schlau-Cohen and Bin Zhang showed that binding with EGF triggers structural shifts activating cellular growth machinery.
The researchers also studied cholesterol's effect on EGFR function by creating nanodiscs with elevated cholesterol levels. They found increased rigidity from cholesterol suppressed EGFR signaling.
The findings suggest new possibilities for targeting tumor growth by altering membrane charge or composition rather than focusing solely on blocking receptors directly. The research was funded by the National Institutes of Health and MIT's Department of Chemistry.
