A mechanism of the PI3KC2A kinase enzyme may have significance for the future development of therapies against cancer, obesity and diabetes, research published in Molecular Cell has found. The study highlights how if specific signaling cascades are misregulated, diseases and metabolic disorders may occur. The identified mechanism may have a crucial influence on such signaling cascades.

The teams from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin and at the University of Geneva pursued an approach based around lipids because cell growth, cell differentiation and the efficacy of hormones such as insulin all depend on the presence of lipids.

Lipids are the building blocks of cell membranes and they also serve as molecular switches in signaling cascades. If signaling cascades are disturbed, diseases such as cancer or metabolic disorders such as obesity and diabetes can occur. The ability to influence the enzymes involved in the biosynthesis of signaling lipids in cells could thus serve as a starting point for the treatment of these diseases.

The researchers analyzed lipid kinase PI3KC2A enzyme in detail. The PI3KC2A kinase enzyme performs crucial functions in receptor uptake, cell division, the release of and signaling by insulin and in angiogenesis.

For the first time, the team of scientists was able to observe the transition of PI3KC2A from the inactive into an active form. Dr. Oscar Vadas describes this mechanism: “In its inactive form, the kinase exists rolled up looking as if it had wrapped its 'arms' around itself. In order to activate the kinase, two specific components of the cell membrane have to be in the same location at the same time. When this happens, the kinase unfolds its 'arms,' and each 'arm' binds to one of the two components.” The activated kinase, within seconds, synthesizes many signaling lipid molecules. In turn, these signaling lipids control the uptake of activated signaling receptors into the cell and thereby regulate processes such as cell growth, division and differentiation.

These findings could be of great importance for basic research as the Berlin/Geneva team has provided molecular insight into the central cellular process of receptor uptake. Moreover, the scientific work presents a major leap toward the pharmacological manipulation of PI3KC2A and related kinases.

“For the first time, we have a handle on a mechanism, which may eventually enable us to alter PI3KC2A lipid kinase activity. This may provide a direct target for therapies," says Professor Dr. Volker Haucke. For example, small molecules that block PI3KC2A activity could serve as anti-tumor agents given that angiogenesis is important for nutrient supply to tumors. The FMP scientists in Berlin are now looking for such agents.

“We have discovered a new promising target and are keen to further explore its therapeutic potential,”says Professor Dr. Haucke referring to the initiated compound search. While the FMP does not develop drugs itself, the institute aims to provide new leads for future drug development. Professor Haucke adds: “In this case, we expect to identify candidate molecules that may at some point in the future become clinically useful.”