What Ancient ERK Relatives Can Teach Us about Cancer

“Resurrecting” the ancestors of key proteins yields evolutionary insights into their role in human cells and in most cancers, a new study finds. The study, published today in eLife, revolves around the function of extracellular signal-regulated kinase (ERK), a protein that determines whether human cells divide and multiply as part of growth. The results suggest that ERK was easily switched on in ancient one-celled creatures but was carefully restrained as the first animals evolved 800 million years ago.

The research team used computer analyses to determine the DNA sequences and related protein structures for ancient ERK relatives. By studying them, the researchers identified two key changes that likely brought ERK under more careful control across evolution.

The team also found that it was surprisingly easy to reverse those evolutionary changes and return ERK to its primitive, very active ancestral state. This becomes important, the researchers say, because a similar process occurs as genetic mistakes convert normal cells into cancer. Modern-day ERK is part of “the most important signaling pathway in human cancers,” along with the other protein switches that get stuck in the “on” position to cause abnormal growth.

“That ERK could continue to function while evolving reveals a flexibility that may explain how human cells evolved 500 different kinases that control all aspects of their biology—and why faulty kinases are so central to cancer growth,” says senior author Liam Holt of NYU. “Genetic changes are required for evolution to proceed, but many enzymes stop working when changes occur. ERK continues to signal.”

Like all proteins, versions of ERK are assembled from combinations of molecular building blocks called amino acids. The growing variety of amino acid structures across the animal kingdom that are now cataloged in databases has made possible a new kind of analysis, say the authors. Researchers can make educated guesses about the amino acids occupying each position in the structures of their common ancestors.

Moving forward, the researchers plan to resurrect a complete set of inferred ancestors for all proteins in the ERK class (kinases) and to screen drug candidates against them. Their plan is based on the hypothesis that some mutations cause cancer because they return kinases to more ancient states that are not properly regulated.