A new study from Weill Cornell Medicine uncovers how a viral protein called E4ORF1 precisely activates a specific signaling complex in human blood vessel cells to support cell survival. The preclinical findings, published November 13 in the Journal of Biological Chemistry, provide a blueprint for how this pathway can be controlled with molecular specificity—an advance that could help make regenerative cell therapies safer and more effective. “Our findings suggest it may be possible to design therapies that mimic E4ORF1’s selective mechanism to improve vascular repair, tissue regeneration or stem cell support while limiting harmful side effects,” said Dr. Shahin Rafii, director of the Hartman Institute for Therapeutic Organ Regeneration and the Ansary Stem Cell Institute, chief of the division of regenerative medicine and the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell, who led the research. First author Dr. Fuqiang Geng, research associate in medicine at Weill Cornell, co-led this research.
Dr. Shahin Rafii
Previous research showed that E4ORF1, a protein produced by certain human adenoviruses, promotes the survival of endothelial cells, which line blood vessels. This discovery led to efforts to incorporate E4ORF1 into regenerative medicine strategies. Umbilical cord–derived endothelial cells engineered to express E4ORF1 are already being explored as supportive “niches” that help stem cells survive and expand outside the body. In clinical trials, these cells are being developed as an off-the-shelf reparative therapy to reduce severe organ toxicities following high-dose chemotherapy.
The new study explains why this approach works at a molecular level. E4ORF1 selectively activates the PI3K–AKT signaling pathway, which is essential for cell survival, metabolism and growth without broadly switching on related pathways that can drive excessive proliferation or cellular exhaustion.
The researchers found that E4ORF1 engages a specific isoform of the PI3K enzyme, which is composed of the catalytic subunit p110α and the regulatory subunit p85β. Isoforms are closely related versions of the same protein that differ slightly in structure and function and often act in different tissues or biological contexts. Because PI3K isoforms play many different roles in the body, indiscriminate activation or inhibition of the pathway can lead to unwanted effects.
Dr. Fuqiang Geng
Using biochemical, genetic and imaging approaches in primary human endothelial cells, the team mapped how E4ORF1 achieves this selectivity. The viral protein binds multiple structural regions of p110α, indirectly targeting p85β and releasing its inhibitory control on p110α. At the same time, E4ORF1 recruits a scaffolding protein called DLG1, which helps position the activated PI3K complex at the cell membrane, where signaling occurs. This coordinated mechanism activates AKT, a molecule that allows the endothelial cells to survive, function and support tissue repair in culture and after transplantation—without triggering parallel growth signals linked to uncontrolled cell division.
By identifying the p110α–p85β complex as a functionally distinct and potentially druggable signaling unit, the study provides mechanistic insight that could inform the design of safer regenerative therapies and future clinical trials. “To help treat disease by targeting p110α‑p85β, we’re working on creating safer, more effective drugs that act like E4ORF1, using advanced structural and computer‑modeling research,” said Dr. Geng. “We also hope that our E4ORF1 work will inspire scientists to target other PI3K isoforms.”