Oak Ridge Researchers ID Proteins that Can Block Tumor Growth Pathway
By Bio-IT World Staff
July 14, 2022 | Researchers at the Department of Energy’s Oak Ridge National Laboratory have definitively linked the function of a specific domain of proteins to the activation—and deactivation—of the c-MET pathway, which leads to the progression of tumor growth and metastatic cancer cells. Mutating any of four proteins blocks pathway progression.
The team’s findings, published in Nature Communications Biology (DOI: 10.1038/s42003-022-03582-8), open up a new avenue for the development of selective drug therapies to fight a variety of cancers such as those that begin in the breast and stomach.
The work represents the experimental testing of a 2019 computational finding: that the plasminogen-apple-nematode, or PAN, domain is linked to both the cell proliferation that drives tumor growth in humans as well as defense signaling during plant-microbe interactions in bioenergy crops. The association was first made as researchers explored the genomes of crops like poplar and willow. (DOI: 10.1371/journal.pone.0202519)
For the latest study, the ORNL team used the InterPro and UniProt databases as well as Gene Ontology enrichment analyses to pinpoint four cysteine residues—conserved across 14 model organisms—in the HGF protein critical to the PAN domain’s function. They hypothesized that these may play a role in HGF and c-MET interaction and downstream signaling.
“The HGF/c-MET pathway has emerged as a prime target for cancer pathways and tumorigenesis,” the authors wrote in the paper. “However, despite the clinical therapeutic significance of this pathway, the mechanism by which HGF activates c-MET is not well understood.”
The team found that mutating any one of the four amino acids in the PAN domain set off a “cascade of negative regulation of HGF/c-MET signaling,” beginning with attenuated HGF degradation and impaired c-MET interaction and ending with a lack of phosphorylation for c-MET and its downstream targets AKT, ERK and STAT3.
Molecular dynamic simulations suggest that the mutations don’t change the overall structure of HGF, but stable cross-linking of c-MET and HGF occurs only in the presence of intact PAN domain in HGF. Mutating other cysteines in the protein had no impact on HGF/c-MET, and mutating the four key cysteines had no other effect on the overall structure of the protein.
“Taken together, the PAN domain and its core cysteine residues are essential for HGF/cMET signaling in human cells,” the authors conclude.
This level of precision is extremely valuable for developing new cancer therapies, said ORNL geneticist and senior author, Wellington Muchero, in a news release.
“It’s very difficult to engineer molecules to interfere with an entire protein,” he said. “Knowing the specific amino acids to target within that protein is a big advancement. You don’t have to search the entire protein; just look for these four specific residues.”
