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MDC researchers discover new regulatory mechanism of important protein

October 07, 2016

Protein kinase A (PKA) is an important signaling enzyme that is found throughout the body and is involved in many cellular processes. It was thought to have been comprehensively studied, but scientists at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) have now discovered a new layer of PKA regulation and published their findings in Nature Communications.

The MDC research team headed by Dr. Oliver Rocks is investigating the mechanisms that control the remodeling of the cell skeleton. During a screen of proteins involved in this process the scientists made an interesting discovery - they noticed that one of the proteins binds the catalytic subunit of the PKA. "We were surprised to find the catalytic subunit of PKA, because normally control of this pathway is through the regulatory subunit," says the researcher.

In the classical model of PKA regulation, the regulatory subunits dock onto the catalytic ones and stop them sending signals. They only release the catalytic subunits when the cell receives a signal that increases the levels of the cellular chemical cAMP. cAMP clips onto the regulatory subunits and force them to set the catalytic subunits free.

In the screen the catalytic subunit of PKA (PKAC) was binding to a protein called ARHGAP36. For her PhD research in Dr. Rocks's lab, Rebecca Eccles investigated how ARHGAP36 interacts with PKAC. She worked with other scientists at the MDC, the Berlin Institute of Health (BIH), as well as partners at the University of Liverpool. Eccles found that ARHGAP36 can turn off PKAC in two ways: by binding to it and blocking its action, and by sending it on the path to one of the cell's degradation centers.

PKA's job in the cell is to pass on signals, which the catalytic subunit does by its kinase action - kinases attach a phosphate molecule to their target proteins (substrates). ARHGAP36 stops PKAC from binding its substrates in much the same way as a key stuck in a lock prevents you opening a door. Because PKA occurs in almost all tissues, the researchers wanted to identify where and when it is inhibited by ARHGAP36. "ARGAP36 is a strong inhibitor, so you wouldn't want it turning off PKA everywhere," Rocks explains. He and his team found that ARHGAP36 is not present in all cells all the time - in fact its expression is quite limited, for example to embryonic muscle cells.

Abnormally high levels of ARHGAP3 are also found in at least one of the four subtypes of medulloblastoma, the most common childhood brain cancer, as well as in neuroblastoma, another frequent cancer of the nervous system in children. The exact biological role of ARHGAP36 is not yet understood, but it may well play a role in muscle development and in tumor progression in some cancers. For example, changes in PKA signaling could influence tumor growth in many types of cancer. Understanding how signaling pathways are controlled may also be useful in drug development since it opens up opportunities for regulating proteins indirectly and thus blocking enzymes that are otherwise hard to manipulate.
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Max Delbrück Center for Molecular Medicine in the Helmholtz Association

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