AI Helps Cornell Team Find Cellular "Off Switch" Linked to Cancer Pathways

Cornell researchers have used artificial intelligence to uncover a previously unknown way that cells control how proteins move inside them — a process essential for growth, communication and movement that is often disrupted in cancer. The study, published September 9 in the Journal of Cell Biology, shows that a little-understood protein called Avl9 acts as an "off switch" for another protein, Arf1, which helps direct where materials go inside cells.

Arf1 acts as a molecular switch that directs proteins and other cargo from the Golgi — a cell structure that packages and ships materials — to other destinations inside the cell, and is essential for secretion, migration and basic internal organization. Because Arf1 is involved in so many cellular pathways, the team, led by Cornell professor Chris Fromme, suspected there had to be more proteins controlling its activity than were already known.

Instead of traditional lab screening, which can take months, the researchers used AlphaFold, an AI program that predicts protein structures and how they might interact, to quickly generate a shortlist of likely partners for Arf1. "We discovered an unexpected function of a poorly understood protein, which helps us understand how cells control intracellular trafficking," Fromme said. The AI analysis pointed to Avl9, a protein previously linked to secretion and cancer cell movement but whose function was unknown.

Laboratory experiments confirmed that Avl9 shuts down Arf1 after it has carried out its role. "The function of Avl9 was the exact opposite of what you would guess based on what was known about its amino acid composition," said Ryan Vignogna, the study's first author. A single amino acid change eliminated Avl9's ability to regulate Arf1, and in human lung cancer cells, that same change reduced the cells' ability to move.

The researchers also examined a broader group of similar proteins, known as DENN domain proteins, which had previously been thought to act only as "on switches." They confirmed that at least one related human protein behaves the same way as Avl9, pointing to a broader, previously unrecognized system that cells use to keep internal transport in balance.