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A basic scientific discovery by researchers at the Johns Hopkins Bloomberg School of Public Health reveals a fundamental way in which cells interpret signals from their environment and may eventually pave the way for potential new therapies.
The discovery involves a signaling pathway in cells, called the hippo pathway, which normally limits cell division and regulates organ size, and also plays a role in tissue growth and development, as well as tumor suppression. The hippopotamus path is so fundamental that it is found in species ranging from humans to flies.
Bloomberg School researchers have elucidated how this signaling pathway works by solving a long-standing mystery about how one of its main components, an enzyme called MST2, can be activated by multiple signaling inputs.
The discovery is reported in an article dated November 20 in Journal of Biological Chemistry.
“We knew this pathway could be activated by several signals upstream, and here we revealed the mechanism by which this happens,” says senior study author Jennifer Kavran, PhD, assistant professor in the Department of Biochemistry and Molecular Biology. Bloomberg School.
The Hippo path normally functions as a brake on cell division that prevents any larger organs once the appropriate size reached. Mutations or other abnormalities in the pathway that take the brakes off cell division have been found in many cancers, making elements of the Hippo pathway potential targets for future cancer treatments.
Because of its pivotal role in tissue and organ growth, the path is also of great interest to researchers who are developing techniques to improve wound healing and stimulate regeneration of damaged tissue.
The heart of the Hippo pathway begins with the activation of two highly related enzymes, and MST1 MST2, which are almost identical and perform overlapping functions. A variety of biological events, including cell-to-cell contacts, certain nutrients, stress, and signaling through cell receptors, can cause activation of MST1 / 2, a process in which the enzyme is labeled with sets of atoms of phosphorus and oxygen called phosphoryl groups.
Once activated by this “autophosphorylation”, MST1 / 2 can send signals downstream to complete the signaling chain and inhibit cell division. Normally, proteins that undergo autophosphorylation are activated by a single molecular “event”, such as the binding of a particular molecule or interaction with another copy of the same enzyme. How such a variety of inputs can trigger MST1 / 2 activation has been a mystery.
“In cell biology, we’re used to the idea that when an enzyme is transmitting a signal, a single molecular event triggered that enzyme,” Kavran says.
In the study, she and her colleagues used test-tube and cell culture experiments with human MST2 to demonstrate that the myriad activators upstream of this enzyme trigger MST2 autophosphorylation in the same way – simply by increasing the local concentration of these enzymes – by reducing thus the distance between enzymatic sites on individual enzymes and facilitating mutual phosphorylation.
The researchers believe their finding could apply not only to MST2 but also to its twin MST1 and very similar versions of the enzyme produced in other species.
Although this was primarily a basic scientific study, the findings should improve researchers’ ability to manipulate Hippo’s pathway signaling, both for basic research and for potential therapeutic applications for tissue regeneration and anti-cancer therapies.
“The techniques we have used to activate MST2 in cell cultures should be useful to other labs that are studying the Hippo pathway and need a way to activate it in a controlled way,” says Kavran.
She and her lab plan to investigate how the other enzymes in the pathway are regulated.
The research was supported by the National Institutes of Health (R01GM134000, T32CA009110, R35GM122569).
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