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Insulin-moderation signal found

Survival depends on effective communication. In cells, molecular signals transmit messages from the cell surface through to where it has its effect. Just as a faulty antenna results in a garbled TV image, if these molecular signals are distorted, messages don’t get through and the outcomes can be catastrophic.

Researchers Alison Kearney and Dr Dougall Norris under the supervision of Dr James Burchfield and Prof. David James from the University of Sydney, and colleagues at the Monash Biomedicine Discovery Institute, have used microscopy at our University of Sydney facility. Combining this with cell biology and mathematical modelling, they have identified a new part of a complex cell communication pathway that controls how insulin signals are conveyed.

Insulin is a potent signal for growth that increases in the body following a meal, to promote the storage of sugar in muscle and fat cells all over the body. If the insulin signal is inadequate, diabetes can develop. Conversely, if the signal cannot be switched off well enough, cancer can develop. Control of this signalling process is therefore crucial to keep our bodies functioning correctly. Understanding how the signals go wrong can really help researchers understand how disease develops and therefore how to design new treatments.

“We have discovered a new part of a cell communication system that prevents the insulin signal from overactivating, just like a thermostat controlling a heater,” Dr Burchfield said.

VIDEO ABOVE SHOWS Explosive growth signals in a glioblastoma (brain cancer cell). A172 cells expressing tagRFPt-AKT (yellow). VIDEO TAKEN USING Spinning disk confocal MICROscopy.

When insulin arrives at the outside of a cell, it sticks onto a special receptor protein that spans the cell membrane, connecting the outside of the cell to the inside. Once insulin has bound to its receptor on the outside, another protein inside the cell sticks onto the inner part of the receptor from where it activates the chain of communication through the cell. The team discovered that as one of the steps along this pathway gets more and more active, it goes back and modifies the protein stuck to the inside part of the receptor. This makes it fall off the receptor, which in turn switches off the insulin signal.

“If cells lost this mechanism, the growth signal would no longer be controlled, and tumours could develop. Some current anti-cancer drugs may actually impair this mechanism and ironically lead to increased tumour growth and drug resistance. Thus, identifying these mechanisms and understanding how they work will aid the development of better cancer therapy,” Dr Burchfield added.

A. L. Kearney et al., eLife 2021 DOI: 10.7554/eLife.66942

 

Confocal image of proteins (white) accumulating at the edges of the cell (purple).