NEW YORK, Aug. 13, 2019 /PRNewswire/ -- "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 online August
13 in the journal 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.
Led by researchers from NYU School of Medicine, the new study
suggests that ERK was easily switched on in ancient one-celled
creatures, but was carefully restrained as the first animals
evolved 800 million years ago.
Specifically, 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 study author
Liam Holt, PhD, assistant professor
in the Institute for Systems Genetics at NYU Langone Health.
"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
now catalogued 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 research team plans to resurrect a complete
set of inferred ancestors for all proteins in ERK's class
(kinases), and to screen drug candidates against them, says Holt.
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.
To avert side effects and drug resistance, he says, future drugs
might be designed to inhibit ancestor-like, cancer-causing kinase
versions without turning off related, normal enzymes.
Along with Holt, authors from the study from the Institute for
Systems Genetics at NYU Langone Health were Dajun Sang and Sudarshan
Pinglay. Also authors were Rafal
Wiewiora and John Chodera of
the Computational and Systems Biology Program at Memorial Sloan
Kettering Cancer Center; Myvizhi Selvan and Zeynep Gumuş in the
Department of Genetics and Genomic Sciences at Icahn School of
Medicine at Mount Sinai; and Hua
Jane Lou and Benjamin Turk in the
Department of Pharmacology at Yale University
School of Medicine.
The study was supported by Perlmutter Cancer Center Support
grant P30CA016087, Department of Defense Horizon Award
W81XWH-17-1-0412, and National Institutes of Health grants
R01GM121505 and P30CA008748. Additional funding for the study came
from the William Bowes Fellows program, the Vilcek Foundation, the
LUNGevity foundation, and the Icahn Institute for Data Science and
Genomic Technology.
Contact: Gregory Williams, (212)
404-3500, gregory.williams@nyumc.org
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SOURCE NYU Langone Health
