Researchers from the University of California, San Diego have identified a new signaling process involving G-protein-coupled receptors (GPCRs), a cellular target already exploited by hundreds of diverse drugs. The discovery, published in the October 26, 2022 issue of Natureopens the possibility of new therapies, including for multiple forms of cancer.
GPCRs are the largest and most diverse group of membrane receptors in eukaryotes -; cells containing a nucleus and other organelles. Residing on the surface of the cell, they act as an inbox for messages arriving in the form of sugars, proteins, lipids, and peptides, and play a myriad of roles in bodily functions, including regulating communications. between cells.
As a result, they have become an important therapeutic target for treating everything from high blood pressure to asthma to acid reflux, with ongoing research into their potential in moderate conditions such as diabetes, obesity and Alzheimer’s disease. It is estimated that more than one-third of all drugs currently approved by the Food and Drug Administration target one or more members of the GPCR family.
“We believe these new findings may change the textbook model of GPCR-mediated signaling,” said study lead author Jin Zhang, PhD, professor of pharmacology at UC San Diego School of Medicine. , professor of chemistry and biochemistry and professor of bioengineering at UC. San Diego Jacobs of Engineering, “and it could have profound implications for future drug development.”
The canonical view of GPCRs is that they sit on the cell membrane where they activate various reactions, including an enzyme called extracellular signal-regulated kinase (ERK), which triggers a cascade of signals to control cell growth and survival. .
But Zhang’s team found that there is virtually no ERK signaling at the cell plasma membrane. In contrast, GPCR-mediated ERK signaling arises from – endosomes; organelles in the cell that sort and help move materials from the surface to internal destinations or help degrade, recycle, and export unnecessary materials. GPCRs are known to be transported through endosomes.
ERK signaling regulates the transcription of a number of genes involved in cell growth control. Dysregulation of ERK signaling has been implicated in several pathologies, including cancer. As such, therapeutic intervention targeting members of the ERK signaling pathway is a major endeavor among cancer researchers.
Despite the important regulatory roles these receptors play in ERK-related signaling, the mechanism underlying GPCR-regulated ERK activation has long been a mystery.
We found that GPCR-mediated ERK signaling, upon activation at the endosome level, propagates into the nucleus, where it activates genes important to control cell growth. Given the closer proximity between endosomes and the nucleus, compared to the plasma membrane and nucleus, cells may be taking advantage of the 3D spatial organization of cell organelles and using a “shortcut” for efficient signal transduction of the receiver.”
Jin Zhang, lead author of the study
The findings challenge the paradigm that GPCR-regulated ERK signals originate from the cell surface. In addition to recent studies showing that active receptors are present inside cells, the authors said, the data demonstrates that GPCR-mediated ERK signaling arises from endosomes involving hormone-bound and activated receptors.
Previous textbook models suggest that GPCRs can signal through two distinct classes of molecules: G proteins and arrestins. Arrestins are intracellular proteins involved in the termination of plasma membrane signaling. They have been shown to play a major role in ERK signaling, but were thought to serve as the scaffolding to enable ERK activation.
The new research suggests greater diversity in how GPCRs signal downstream.
“Our data strongly support the involvement of arrestin in ERK activation, but through its ability to help internalize the receptor and not as a scaffold for ERK as previously thought,” said co-author Roger Sunahara, PhD, professor of pharmacology at UC San Diego School of Medicine.
Zhang added that the new work suggests that arrestins and G proteins work together to activate ERK at the endosome level, with arrestins escorting receptors to endosomes and G proteins recruiting the ERK activation machinery.
“There are broad implications for basic and translational science given the large number of GPCRs involved in transmitting various cellular messages to regulate bodily functions,” Zhang said.
“An immediate implication is the potential generality of the proposed model, which should be investigated beyond the few receptors we investigated in this work. In terms of translational impact, GPCR drug development has been influenced by concepts such as “biased signaling,” with drugs developed to preferentially activate G-proteins or arrestins The discovery that certain receptors require the collaboration of arrestins and G-proteins to activate ERKs is expected to change the way GPCR drugs are developed.
Many types of cancers contain mutations in G proteins that contribute to cancer development, said J. Silvio Gutkind, PhD, professor emeritus and chair of the department of pharmacology at UC San Diego School of Medicine and co-director of basic sciences. in the Hanna and Mark Glieberman Head and Neck Cancer Center at the UC San Diego Moores Cancer Center.
“Many tumors harbor persistently active G proteins and GPCRs, including colon, pancreatic and appendix cancers. The new findings can now be exploited to develop new treatment strategies to prevent and treat these human malignancies.
Co-authors include: Yonghoon Kwon, Sohum Mehta, Mary Clark, Geneva Walters, Yanghao Zhong, and Ha Neul Lee, all at UC San Diego.
University of California – San Diego
Kwon, Y. et al. (2022) Noncanonical β-adrenergic activation of ERK at the level of endosomes. Nature. doi.org/10.1038/s41586-022-05343-3.