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Kate Carroll Challenges Conventional Wisdom

By Eric Sauter

Kate Carroll turned heads lately with her most recent study in the journal Nature Chemical Biology. In that study, Carroll, an associate professor at Scripps Florida, upended conventional wisdom regarding aspects of the oxidation process, which basically came down to a single word: bad.

The new study focuses on a little appreciated and wildly understudied cell modification mechanism called sulfenylation, which has a much more important role to play in the regulation of signaling proteins than had been previously considered.

It works like this. During periods of chronic stress, which can be brought about by everything from too much exposure to UV radiation to diseases such as cancer, the level of reactive oxygen-containing molecules—known as reactive oxygen species or ROS—increases, causing an impressive amount of damaging protein modification, all of which does the cell itself no good.

One oxidant in particular, hydrogen peroxide, functions as a messenger that activates cell proliferation through oxidation of cysteine residues in signaling proteins, producing sulfenic acid, a process called sulfenylation; cysteine, an amino acid (natural protein building block), is highly oxidant sensitive.

Up until Carroll’s new study, conventional wisdom was that if hydrogen peroxide existed in large quantities in the cell, it was indicative of a disease or highly stressed state and there was nothing positive about those high levels. (see

But Carroll thought differently and the new study not only confirms her belief, but does so in a spectacular fashion.

New Regulatory Responsibilities

The new study shows for the first time that sulfenylation is something more than a stress marker and much, much more than just a mean motor scooter and a bad go-getter. Carroll and colleagues have shown that the process is a global signaling mechanism that bears an extraordinary resemblance to phosphorylation, the regulatory insertion of a phosphorous group into a protein that turns it on or off. Phosphorylation has long been considered the sine quo non of regulatory factors in a range of critical cell signaling processes from cell metabolism to programmed cell death.

Not anymore.

“With this paper, we’ve elevated protein sulfenylation from a marker of oxidative stress to a bona fide reversible post translational modification that plays a key regulatory role during cell signaling,” said Carroll. “The sulfenyl modification is the new kid on the block.”

The new study proves that sulfenylation is actually a positive modification of the protein in question, and that it’s required for signaling through the pathway, not merely as an oxidative delinquent to be eliminated at all costs. This and other studies have contributed to a new picture of hydrogen peroxide.

“We show that NOX, an enzyme that generates hydrogen peroxide not as a by-product, but as its primary function, co-localizes with the receptor that initiates a signaling cascade leading to cell growth,” said Carroll. “These proteins become associated following stimulation of cells with growth factor and their close proximity leads to receptor modification and modulation of kinase activity.”

A Novel Technology

What’s even better is that Carroll has produced a technology that can show where this sulfenylation modification is happening on which proteins. A highly selective chemical probe with the Star Wars-like moniker of DYn-2 can now detect minute differences in sulfenylation rates within the cell.

“When you inject cells with hydrogen peroxide, you can see that see that signaling pathways are altered but the link that’s been missing for so long is the underlying molecular mechanism,” she said. “This is where our technology is critical. It allows us to probe and trap these modifications directly in the cellular context, not in some artificial system, and it’s the only technology in the field that does that without inhibiting the pathway. With it we can label enough modifications so we can basically figure out which proteins are being modified.”

In the new paper, Carroll used the technology to identify the site of modification in cells, as well as the extent of the modification, which is about 75 percent.

This will have an impact not only within the science of protein modification, but also in the area of future drug design.

“From an applied standpoint, it should influence the design of inhibitors that target oxidant-sensitive cysteines,” she said. “We need to think strategically about the reactive moiety that we use to covalently modify a cysteine residue because if the thiol group is chronically oxidized, its chemical properties are different, which can neutralize the effectiveness of the conventional approach. The implication here is very broad: how is inhibitor potency affected by oxidation and, taking this one step further, could you exploit the propensity for oxidation to develop a new class of therapeutics?”

While all that may lie in the future, Carroll is currently enjoying the robust applause of the redox signaling community.

“The number of seminars I’ve given over the past year has increased significantly,” she said. “It’s one thing to talk about clever chemical tools from an academic perspective, but to go in front of a biological community—often where the rubber meets the road—and to have them get excited about our research, that’s thrilling.”

Musical Beginnings

A native of California born south of San Jose in a rural agricultural community—her family grew fruit trees and she worked the orchards as a child—Carroll was interested in sports and music, eventually narrowing that down to playing the oboe, and taking that all the way to the San Francisco Conservatory of Music.

“My first year at the conservatory I looked around at all these starving master’s students and thought, ‘Man, what am I in for?’” she said.

She soon transferred to a small liberal arts college in Oakland and got her first lab job at Oregon State University. That was the start of it all.

“I’m pretty particular and precise about things,” she said and then added, somewhat mischievously, “and a bit obsessive. It was a clear pathway to me—science—if I kept working in the lab, I could go to graduate school and the beauty of graduate school is that they pay you to learn. That seemed like a great plan to me.”

While developing her career in science, she has been careful in choosing her role models.

“Having role models of women in leadership roles has been very reinforcing,” she said. “My graduate advisor at Stanford, Suzanne Pfeffer, is a leader in the field of protein transport and the current president of ASBMB—and then I went to work for Carolyn Bertozzi at Berkeley, an HHMI investigator who is a luminary in the field of chemical biology research. Both are female scientists working in an academic environment, with successful lives from a professional and personal point of view.”

Carroll made her decision for science at 17; one almost images it as a sheer force of will. Now she has children of her own—her oldest daughter is seven—and with that comes the realization that it doesn’t necessarily get easier.

“In terms of discipline, making enough time for work and family is a conscious process every day,” she said. “It has to be planned and I need to operate efficiently, just like anyone juggling family and work. Of course, it is really important to have strong support from your family. In my case, I am very fortunate to have an equal partner in everything, someone to share the joys and responsibilities that come with parenthood and a career.”

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"To go in front of a biological community—often where the rubber meets the road—and to have them get excited about our research, that’s thrilling," says Associate Professor Kate Carroll. (Photo by James McEntee.)