No longer a dead end: Shant D. Hinton placed an early-career bet on the study of pseudophosphatases, a class of enzymes that were long thought to be intracellular layabouts. Her lab and others are revealing intriguing disease-related functionalities of pseudophosphatases. Photo by Stephen Salpukas

by Joseph McClain | November 17, 2020

Shant D. Hinton, in the good, old pre-COVID days, delivered what is possibly the worlds first scientific lecture on proteins to incorporate a call-and-response format.

Hinton, an associate professor in William & Marys Department of Biology, had the audience at the universitys 2017 Tack Faculty Lecture calling out kinases! and phosphatases! It was her introduction to the biochemical assembly of enzymes known as phosphatases to a largely lay audience.

Her lab was a pioneer in the study of a group of enzymes known as pseudophosphatases, particularly one known as MK-STYX. Pseudophosphatases were long considered a research dead-end, but Hinton and a handful of other labs discovered that there was nothing pseudo about these proteins.

Im still preaching the gospel of MK-STYX, she said in a recent interview. I will continue that until the day I die. But I am looking forward to adding more pseudophosphatases to my research program.

The gospel of MK-STYX is spreading. Her labs work on the protein is supported by funding from both the National Institutes of Health and the National Science Foundation. Hinton is the author of Pseudophosphatase MKSTYX: the atypical member of the MAP kinase phosphatases, which was featured prominently in The FEBS Journal, a publication of the Federation of European Biochemical Societies.

The FEBS Journal piece is a review article, in essence an overview of investigations, discoveries and prospects of pseudophosphatases, MK-STYK in particular. Hinton explains that she first became interested in MK-STYX when she was a Ph.D. student at Howard University. She kept seeing intriguing papers on pseudophosphatases during her postdoc and early career years.

A phosphatases job is to attach to a phosphate group in a protein, then delete it. The action changes the proteins functionality. For years, the common perception was that pseudophosphatases were the lazy brothers-in-law within the cellular world: they would grab on, and hold on, to the phosphate group. But they wouldnt finish the job of deletion.

Hinton said labs such as Jack Dixons at UC San Diego were publishing evidence that pseudophosphatases werent so very pseudo after all. And then, another paper came out that said an MK-STYX variant was implicated in the development of Ewing sarcoma, a pediatric cancer. Hintons lab began drilling down into what MK-STYX actually does.

We began to put the functionality of MK-STYX on the map, she said. My lab gave the scientific community phenotypes to look at MK-STYX and one of those phenotypes is that it can induce neurites.

Neurites, Hinton explained, are the first stages in the development of neurons, those specialized cells that communicate with other cells through connections known as synapses. She added that another contribution of her lab was to discover MK-STYXs role in the cells stress response pathway, as it tends to decrease the number and size of stress granules.

When cells become stressed by any number of environmental factors, they have a protection mechanism, which is stress granules, she said. However, if the activity of the stress granules becomes prolonged, it could lead to neurological disorders.

The discovery of those two functions of MK-STYX opened doors of research possibilities for Hintons lab. They can proceed to more detailed structural studies.

And its great timing, because now we have the funding to look at both projects, she said.

Thanks to Hinton and a few other researchers, pseudophosphatases are no longer seen as a dead end. MK-STYX and its variant STYXL1 are being investigated by some high-throughput research labs for connections to diseases ranging from arthritis to diabetes, and even cancer and neurodegenerative disorders.

Hintons lab in William & Marys Integrated Science Center has traditionally been staffed largely with undergraduates. Now, she has three masters students and the NSF funding has allowed her to hire Lynn Zavada as a lab technician. She said her lab continues to be productive during COVID times.

The situation is challenging, she said. But my department has been very gracious. If we write certain protocols and complete certain forms, we can be in the lab. Weve been in the lab since August.

Hinton acknowledges that things were very slow in the spring and early summer, when she had limited access to the lab. She pointed out that her work, like that of many biologists, is heavily wet bench, which means they need to be in the lab to work. She took advantage of the slow March to July period by sharpening her own computational skills as well as those of her students.

I went back and addressed evolutionary questions and other aspects that require a computational approach, Hinton said. I gave a couple of students those types of projects, too. Hopefully, with the next year or really less well be publishing from that aspect.

She picked undergrads who are majoring in computer science or CAMS computational & applied mathematics and statistics for the computational projects. She meets with them weekly.

And I force myself to learn things, she said. So that I can communicate with them and tell them what I want. It also helps me for when I communicate with other labs that have more-computational approaches.

Hinton expanded her renewed interest in the computational side of biochemistry by creating a graduate-level bioinformatics class. The class meets in-person every Wednesday. Each student selects a gene or protein of interest to work on together. Its a learning experience for the professor as well as the students, she says.

Its active learning. Were learning together, she said. We have to struggle through this, because we dont want to sit at home. I didnt think that I would teach this course permanently, but after seeing how well its gone, maybe I will.

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Nothing 'pseudo' about them: Drilling down into the function of pseudophosphatases - William & Mary News