AI reveals new class of cellular 'off switch' linked to cancer pathways

Cornell researchers have utilized artificial intelligence to unveil a novel mechanism by which cells regulate protein movement within their structures, a process crucial for growth, communication, and movement that is frequently compromised in cancer. Their findings, published on September 9 in the Journal of Cell Biology, demonstrate that a protein named Avl9 functions as an "off switch" for Arf1, another protein that guides where cellular materials are transported.

Proper regulation of Arf1 is vital for maintaining cellular organization; otherwise, cells may become disorganized, leading to detrimental effects. The researchers discovered that Avl9 is part of a larger family of proteins that may carry out the same function, indicating an unrecognized cellular system for maintaining this balance.

Using AlphaFold, an AI program that predicts protein structures and interactions, the team quickly identified potential Arf1 partners, bypassing the months-long traditional lab screening process. They found that Avl9 unexpectedly functions as an "off switch" for Arf1, halting its activity after it has fulfilled its delivery role.

This unexpected function, contrary to Avl9's presumed role in secretion and cancer cell movement, was confirmed through laboratory experiments where a single amino acid change in Avl9 eliminated its ability to regulate Arf1. The researchers also observed that in human lung cancer cells, this mutation reduced cell movement, linking Avl9's molecular role to a behavior associated with cancer.

Further investigation revealed that other proteins within a group called DENN domain proteins, previously thought to function as "on switches," can also act as "off switches" like Avl9, suggesting a broader system in cells for regulating internal transport. This discovery may aid researchers in understanding how disruptions in this system contribute to diseases, particularly cancer.