The researchers have shown for the first time that a specific enzyme is responsible for sensing the available supply of GTP, an energy source that fuels the uncontrolled growth of cancer cells.
The researchers showed that the enzyme PI5P4Kβ (phosphatidylinositol-5-phosphate 4-kinase-β) acts like the arrow on a fuel gauge. The enzyme senses and communicates (signals), via a second messenger, the amount of GTP fuel that is available to a cell at any given time. Until now, the molecular identity of a GTP sensor has remained unknown.
GTP--guanosine triphosphate--is one of two energy molecules used by cells. The other is ATP (adenosine triphosphate). ATP handles the bulk of a cell's energy requirements, while GTP is required for protein synthesis and is a signaling molecule that helps direct processes within the cell. When GTP levels are increased and utilized as fuel by rampaging cancer cells, its ability to perform its primary goals is compromised.
The team identified PI5P4Kβ as a GTP sensor by demonstrating, in a laboratory setting, its ability to bind to GTP and by demonstrating, at the atomic level by X-ray structural analysis, the molecular mechanism by which it recognizes GTP. They then designed PI5P4Kβ mutant cells that were unable to sense GTP concentration and, as a result, impaired the ability of PI5P4Kβ to promote tumor growth.