Probing protein’s role in cell biology to understand how it might fight cancer

Researchers from Lehigh University, the University of Virginia, and Massachusetts Institute of Technology have joined forces in an effort to unlock the mysteries of a protein that plays a crucial regulatory role in human health and disease. Understanding the protein’s function could lead to better therapies for cancers and other diseases.

Funded by a $1.6 million Project Research Grant from the National Institute of General Medical Sciences of the National Institutes of Health, Damien Thévenin, associate professor of chemistry at Lehigh, leads the effort with co-principal investigator Matthew Lazzarra, associate professor of chemical engineering at the University of Virginia. They are joined by collaborating investigator George White at the Massachusetts Institute of Technology.

At the center of the team’s focus is a protein known as protein tyrosine phosphatase receptor type J (PTPRJ), a member of the family of receptor-like protein tyrosine phosphatases (RPTP), which target and dephosphorylate, or deactivate, proteins involved in cell proliferation and survival. The team envisions that their work on the PTPRJ protein will provide expanded insights that are relevant across the receptor-like protein tyrosine phosphatase family.

Thévenin has dedicated his career to understanding and manipulating to good effect the countless collections of biochemical compounds at the cellular level. The problem is elementary, he says. “How do you go from an outside stimulus to a response in an organism? How do cells respond?” From there, complications increase exponentially. “Essentially, this begins a cascade of events inside the cells that allow the cells to respond in very specific ways. You may have tens or hundreds of different proteins and molecules inside the cell that interact with each other,” he explains. “You can view this as a network, with an extremely complicated mesh of interactions. It’s highly complex and crazy, but it’s fascinating.”

Current treatment protocols that target tumor-promoting kinases are limited to pharmacological inhibitors and antibodies, Thévenin says. While some drug treatments can be highly effective, at least initially, resistance to these inhibitors virtually always arises through mutations or bypass signaling via alternative receptor tyrosine kinases. Promoting the activity of RPTPs could be an effective alternative approach to overcoming common acquired resistance mechanisms, as it should be immune to the effects of gatekeeper mutations.

“Mutations in growth hormone receptors within cancer cells can blunt the effectiveness of cancer drugs,” Thévenin says. “This development of resistance happens in most cancers and drugs become ineffective after a relative short period, resulting most often in patient relapse. Since our peptides do not target directly those receptors that are the most susceptible to mutations in cancers, we expect that our strategy will bypass the development of resistance.”

Lazzara is widely renowned for his prolific research in cell signaling and cellular decision-making. White will contribute to the project by using mass spectrometry to quantify protein phosphorylation events that change in response to modulating PTPRJ function in the lab. Use of mass spectrometry to quantify signaling protein phosphorylation is an area of expertise for which he is well known.

A second project goal is to identify the circumstances under which interfering with PTPRJ dimerization might be most effective for changing how cells function. The broader efficacy of Thévenin’s research, the possibility that it could combat many different types of cancers, is a tantalizing one, but it is a difficult puzzle to solve given the intricate landscape of the biological interactions inside the body. “It’s too early to tell, but that’s one of our main questions. What happens when we activate PTPRJ or other RPTPs ? Do we see the same responses in every type of cancer cell? What other effects are there? You may put out one fire here but start another one over there,” Thévenin says.

“My guess is it will be specific not to particular cancers but to certain cancer profiles. This is important to know to identify cancers that may be more susceptible to our peptides. The other promising possibility is combining our peptides with approved drugs. We expect that treating cancer cells with our peptides will reveal weaknesses that can be exploited to improve the efficacy of existing therapies. We’re looking into that as well both in vitro and in animal models.”

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