A team of scientists from the University of California San Diego has pinpointed the reason behind a cellular pathway “short-circuit.” This breakthrough sheds new insight on the development of various human diseases and has the potential to pave the way for the creation of numerous new medications. The findings were documented in a recent issue of the journal Science Signaling, where the study delves into the biochemical process that can disrupt cellular communication.The authors of the paper, Pradipta Ghosh, M.D., and Irina Kufareva, Ph.D., have described a disruptive interaction in cellular pathways as a game-ending “buzzer.” Ghosh is a professor in the Departments of Medicine and Cellular and Molecular Medicine at University of California San Diego School of Medicine, while Kufareva is an associate professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego.
Their paper discusses the “cross talk” mechanism between two cellular pathways. The first pathway is initiated by proteins called growth factors and their cellular receptors, while the second pathway is mediated by a complex.The G protein-coupled receptors (GPCRs) are a distinct set of cellular receptors that transmit molecular signals from the outside to the inside of the cell, causing the cells to undergo changes. Kufareva mentioned that approximately 34% of all drugs approved by the U.S. Food and Drug Administration target members of the GPCR family.
She explained that GPCRs are significant drug targets because they are involved in signaling pathways related to various diseases, including mental and endocrinological disorders, viral infections, cardiovascular and inflammatory conditions, and cancer.
Another set of receptors, the growth factors, also play a crucial role in signaling pathways. Both GPCRs and growth factors are essential in mediating cellular responses to external stimuli.Important communication pathway within the cell that promotes cell growth and division. While GPCRs use intracellular molecular switches (G proteins), growth factor receptors are typically believed to bypass these switches. However, Ghosh and Kufareva recognized a potential conflict between the two pathways that researchers had been suspicious about, and through thorough research, the UC San Diego team was able to identify it.
Ghosh explained that the conflict arises from problematic phosphorylation, which is the attachment of a phosphate group to the G protein molecule. The team utilized advanced mass spectrometry techniques to map all.In a study on G proteins, researchers investigated the impact of phosphoevents, which are the sites on G proteins that become phosphorylated when cells are stimulated by growth factors. They examined how these phosphoevents affected the ability of G proteins to carry out their normal function downstream of GPCRs.
The results showed that almost all phosphoevents on the G protein had a negative impact on various aspects of GPCR signaling. This was attributed to the distortion of the G protein structure caused by these phosphoevents. Essentially, the growth factors “steal” G proteins from GPCRs, effectively paralyzing their signaling.g.”
Additional examination of the phosphoevents demonstrated that a solitary amino acid was responsible for the theft of the G protein. Ghosh stated that the tyrosine amino acid, located at position 320 within the G protein, was situated on the side of the G protein that comes into contact with G protein-coupled receptors.
“Almost a decade ago, this specific tyrosine was recognized as a special ‘trigger point’ for G protein-coupled receptors to transmit their signals. We started contemplating the significance of this coincidence,” Ghosh explained. “That’s when we had a realization: If cell communication could be manipulated at this precise location by a virus or a cell, it would essentially compromise the integrity of the whole process.”The analogy used by Kufareva and Ghosh to explain their discovery is like a game where the tyrosine at position 320 on the G protein acts as a buzzer. If growth factors phosphorylate this site first, then the G protein-coupled receptors have no chance. This discovery has important implications for the development of new therapies, particularly for conditions like cancer. Ghosh mentioned that many pharmaceuticals target G protein-coupled receptors and are effective in treating various diseases. However, there are still conditions like fibrosis, chronic inflammation, and certain cancers that lack effective drug therapies.The interaction between these two pathways is not yet fully understood. According to Ghosh, the findings are expected to be significant and timely, and will contribute to other studies focusing on these major signaling pathways. Kufareva added that the work is particularly relevant as growth factors, their receptors, and G-protein-coupled receptors are highly co-expressed in many cancers. All authors of the paper are affiliated with UC San Diego, including Suchismita Roy, Saptarshi Sinha, and Ananta James Silas from the School of Medicine.The Department of Cellular and Molecular Medicine at UC San Diego is where Pradipta Ghosh is affiliated, and Majid Ghassemian is a member of the Department of Chemistry and Biochemistry, Biomolecular and Proteomics Mass Spectrometry Facility.
Funding for this paper was provided by the National Institutes of Health (CA238042, AI141630, CA100768 and CA160911 to Pradipta Ghosh; R21 AI149369, R01 GM136202, R21 AI156662, and R01 AI161880 to Irina Kufareva). Saptarshi Sinha received support from the American Association of Immunologists Intersect Fellowship Program for Computational Scientist and Immunobiologists.
