Measuring the level of EGFR phosphorylation (overlapping red and green fluorescence) in single cells reveals how cells use a mechanism similar to working memory to navigate. Image credit: Robert Lott (CC BY 4.0)
If we are injured, or fighting an infection, cells in our body migrate over large distances to the site of the wound or infection to act against any invading microbes or repair the damage. Cells navigate to the damaged site by sensing local chemical cues, which are irregular, conflicting and change over time and space. This implies that cells can choose which direction to travel, and stick to it even if the signals around them are disrupted, while still retaining the ability to alter their direction if the location of the signal changes. However, how cells are able to effectively navigate their way through this field of complex chemical cues is poorly understood.
To help resolve this mystery, Nandan, Das et al. studied the epidermal growth factor receptor (EGFR) signaling network which controls how some cells in the body change shape and migrate. The network is activated by specific chemical cues, or ligands, binding to EGFR proteins on the cell surface. The receptors then join together to form pairs, and several tags known as phosphate groups are added to each molecule. This process (known as phosphorylation) switches the receptor pair to an active state, allowing EGFR to relay signals to other proteins in the cell and promote the activity of receptors not bound to a ligand. The phosphorylation state of EGFRs is then modulated over time and across the cell by a network of enzymes called phosphatases which can remove the phosphate groups and switch off the receptor.
To study EGFR phosphorylation dynamics in human cells, Nandan, Das et al. imaged individual cells over time using a microscope. This data was then combined with a mathematical model describing the EGFR signaling network and how cells change their shape over time.
The experiment revealed that the phosphate groups attached to EGFR are not removed immediately when the chemical cue is gone. Instead, the active state is transiently maintained before complete inactivation. This had the effect of encoding a short-lived memory in the signaling network that allowed the cells to continue to migrate in a certain direction even when chemical cues were disrupted. This memory state is dynamic, enabling cells to adapt direction when the cue changes location.
The findings of Nandan, Das et al. reveal the underlying mechanism for how cells decipher complex chemical cues to migrate to where they are needed most. The next steps to follow on from this work will be to understand if other receptors involved in migration work in a similar way.
