Researchers at the University of California San Diego have discovered the cause of a “short-circuit” in cellular pathways, shedding new light on how various human diseases start.
The study, published in the journal Science Signaling, uncovers a biochemical mechanism that disrupts cellular communication, likened to a game-ending “buzzer” by Pradipta Ghosh, M.D., one of the lead researchers.
Ghosh, a professor at UC San Diego School of Medicine, and Irina Kufareva, Ph.D., an associate professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, led the study.
They explored the interaction between two cellular pathways: one driven by growth factors and the other by G protein-coupled receptors (GPCRs).
GPCRs are crucial targets for about 34% of drugs approved by the U.S. Food and Drug Administration because they play a role in many diseases, including mental disorders, infections, heart conditions, and cancer.
Growth factors stimulate a different communication pathway inside cells, promoting cell growth and division.
While GPCRs use molecular switches called G proteins, growth factor receptors were thought to bypass these switches.
However, Ghosh and Kufareva found that these pathways conflict with each other.
The conflict arises from phosphorylation, where a phosphate group attaches to the G protein molecule. Using advanced mass spectrometry, the researchers mapped where these phosphate groups attached to G proteins when stimulated by growth factors.
They then checked how this affected the G proteins’ ability to function with GPCRs.
“We found that phosphorylation events caused by growth factors negatively impacted GPCR signaling,” said Kufareva. “These events distorted the G protein structure, effectively ‘stealing’ G proteins from GPCRs and paralyzing their signaling.”
Further tests revealed that a single amino acid, tyrosine, located at position 320 on the G protein, was responsible for this disruption.
“This specific tyrosine was identified almost a decade ago as crucial for G protein-coupled receptor signaling,” Ghosh explained. “We realized that if growth factors phosphorylated this site first, GPCRs couldn’t function.”
The discovery has significant implications for developing new therapies for diseases like cancer, fibrosis, and chronic inflammation.
Many drugs target GPCRs and are effective in treating various conditions, but some diseases lack good treatments due to the previously misunderstood interaction between these pathways.
“Our findings are important and timely, contributing to other studies on these major signaling pathways that control nearly every process in our cells,” said Ghosh.
“Growth factors, their receptors, and GPCRs are highly co-expressed in many cancers, making our work especially relevant,” added Kufareva.
This research was conducted by a team from UC San Diego, including Suchismita Roy, Saptarshi Sinha, Ananta James Silas, and Majid Ghassemian.
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