Some binding proteins inhibit an important metabolic drive that causes cancer and developmental brain disorders.
Scientists have discovered this molecular mechanism that could open up new opportunities for personalized treatments for cancer and neuronal diseases. They published their results in the journal Cell.
The signal protein MTOR is a sensor for nutrients such as amino acids and sugars. When enough nutrients are available, MTOR speeds up the metabolism and ensures that sufficient energy and cellular building blocks are available. Since MTOR is a central key to metabolism, errors in its activation lead to serious illness. As a result of the malfunction of MTOR, nervous system cancers and developmental disorders that cause behavioral disorders and epilepsy may occur.
Therefore, the cell controls MTOR activity very precisely with the help of suppressors. Suppressors are molecules that inhibit (suppress) a protein and help regulate its activity. The TSC complex is such a suppressor for MTOR. It gets its name from tuberous sclerosis (TSC), the disease that caused its absence. The TSC complex is found together with MTOR in small structures called lysosomes in the cell where it controls MTOR. If the TSC complex no longer remains in the lysosome due to changes in one of its components, this can lead to excessive MTOR activity with serious health consequences.
Protein with an anchor function
Researchers explored how the TSC complex binds to lysosomes. They discovered that G3BP proteins are located on lysosomes along with the TSC complex. "There, G3BP proteins form an anchor that allows the TSC complex to bind to lysosomes." he explains. This anchor function plays a very important role in breast cancer cells. If the amount of G3BP proteins is reduced in cell cultures, this not only leads to an increase in MTOR activity but also increases cell migration.
Drugs that inhibit MTOR prevented this spread, researchers were able to demonstrate this in cell cultures. In breast cancer patients, low G3BP levels are associated with a worse prognosis (indicating a higher likelihood of recurrence of the disease). "Markers such as G3BP proteins can help customize treatments based on MTOR inhibition," says Kathrin Thedieck. he explains. The good thing is that drugs that inhibit MTOR are already approved as cancer drugs and can be specifically tested in further studies.
G3BP proteins also inhibit MTOR in the brain. Researchers have observed impairments in brain development in the absence of G3BP in zebrafish, an important animal model. This leads to neuronal hyperactivity similar to epilepsy in humans. These neuronal discharges can be suppressed with drugs that inhibit MTOR. "Therefore, we hope that patients with dysfunctions and rare hereditary neurological diseases in which G3BP proteins play a role will benefit from drugs against MTOR," said Christiane Opitz. says.
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