Super-resolution microscopy image showing EGFR (cyan), PI(4,5)P2 (magenta) and another lipid called phosphatidylserine (yellow) are distributed non-randomly with partial overlap in the cell membrane. Image Credit: Mitsuhiro Abe and Yasushi Sako (CC BY 4.0)
Residing on the surface of cells are proteins called receptors, which bind to external molecules. Once activated, receptors undergo various changes that allow them to relay the signal to other components inside the cell that can alter the cell’s behavior.
One such protein is the epidermal growth factor receptor (or EGFR for short), which helps regulate cell division and development. When molecules bind to an EGFR, this causes the receptor to attach to another EGFR in the membrane to form a dimer. This dimerization is crucial as it allows the two receptors to add chemicals known as phosphates to each other, which recruit additional proteins that relay the activation signal to downstream targets inside the cell.
Studies have shown that a lipid which sits within the cell membrane, called PI(4,5)P2, helps stabilize the EGFR dimer and aid its activation. However, it is not fully understood exactly how PI(4,5)P2 achieves this.
To investigate, Abe et al. used a super-resolution microscope that can visualize single molecules to examine how PI(4,5)P2 lipids are distributed around the receptor. This revealed that EGFR and PI(4,5)P2 overlap one another to form structures termed ‘nanodomains’ before the receptor is stimulated. Further experiments showed that the nanodomains promote dimerization and activation of EGFRs. They also provide a surface for downstream molecules to dock on to, making it easier for them to relay signals into the cell.
Abe et al. found that once an EGFR has been stimulated, PI(4,5)P2 is broken down by downstream molecules. This results in fewer nanodomains and induces a process that deactivates the signaling pathway.
The findings of Abe et al. suggest that PI(4,5)P2 enhances EGFR signaling by forming nanodomains which are then dissolved once the receptor has been activated. This aligns with previous studies showing lipids in the cell membrane influence the behavior of receptors similar to EGFRs.
The gene for EGFR, and the receptor itself, have both been shown to display abnormal activity in various human cancers. In the future, the work of Abe et al. may provide new insights into how nanodomains influence this irregular signaling, potentially aiding researchers in discovering new cancer treatments.
