A group of researchers at University of California San Diego has identified the cause of a “short-circuit” in cellular pathways, a discovery that sheds new light on the genesis of a number of human diseases.
The recent study, published in the journal Science Signaling, explores the biochemical mechanism that can interrupt the cellular communication chain—a disruptive interaction that Pradipta Ghosh, M.D., likens to a game-ending “buzzer.”
Ghosh, a professor in the Departments of Medicine and Cellular and Molecular Medicine at University of California San Diego School of Medicine, and Irina Kufareva, Ph.D., an associate professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego, are the corresponding authors on the paper.
The paper explains the mechanism of “cross talk” between two cellular pathways, one initiated by proteins known as growth factors and one by their cellular receptors. The second pathway is mediated by a completely different G protein-coupled set of cellular receptors (GPCRs). Both classes of receptors deliver molecular messages from outside to inside the cell and signal cells to change in some way. Kufareva says that members of the GPCR family are targets of around 34% of all the drugs approved by the U.S. Food and Drug Administration.
“GPCRs are important drug targets mainly due to their involvement in signaling pathways related to many diseases,” she explained, citing mental and endocrinological disorders, viral infections, cardiovascular and inflammatory conditions, and even cancer.
Growth factors enable a second, equally important communication pathway inside the cell that makes the cells grow and divide. Whereas GPCRs act through intracellular molecular switches (G proteins), growth factor receptors are conventionally thought to bypass the switches. However, Ghosh and Kufareva note that researchers had been suspicious about some kind of a potential conflict between the two pathways, and careful research allowed the UC San Diego team to identify it.
Ghosh said the conflict stems from problematic phosphorylation, the attachment of a phosphate group to the G protein molecule. She explained that the team used advanced mass spectrometry techniques to map all occurrences of phosphoevents, the sites on G proteins that were phosphorylated when cells were stimulated by growth factors. Then they checked how this changed the ability of G proteins to perform their normal job downstream of GPCRs.
“Whatever aspect of GPCR signaling we looked at, it was negatively impacted by almost all phosphoevents on the ‘switch' protein—the G protein—that would be introduced by growth factors,” Kufareva said. “That was understandable when we looked at how these phosphoevents distorted the G protein structure. Growth factors effectively ‘steal' G proteins from GPCRs and in this way paralyze their signaling.”
Source: University of California – San Diego