Discovery illuminates how cell growth pathway responds to signals

November 20, 2020

A basic science discovery by researchers at the Johns Hopkins Bloomberg School of Public Health reveals a fundamental way cells interpret signals from their environment and may eventually pave the way for potential new therapies.

The finding involves a signaling pathway in cells, called the Hippo pathway, which normally constrains cell division and regulates the size of organs, and also plays a role in tissue growth and development as well as tumor suppression. The Hippo pathway is so fundamental that it is found in species ranging from humans to flies.

The Bloomberg School researchers clarified the working of this signaling pathway by solving a long-standing mystery of how one of its core components, an enzyme called MST2, can be activated by multiple signaling inputs.

The discovery is reported in a paper on November 20 in the Journal of Biological Chemistry.

"We knew that this pathway could be activated by different upstream signals, and here we've revealed the mechanism by which that happens," says study senior author Jennifer Kavran, PhD, assistant professor in the Bloomberg School's Department of Biochemistry and Molecular Biology.

The Hippo pathway normally works as a brake on cell division that stops organs from growing larger once they have reached the appropriate size. 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.

Due to its fundamental role of tissue and organ growth, the pathway also is of great interest to researchers who are developing techniques to improve wound healing and stimulate the regeneration of damaged tissue.

The heart of the Hippo pathway begins with the activation of two highly related enzymes, MST1 and 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 MST1/2 to become activated--a process in which the enzyme becomes tagged with sets of phosphorus and oxygen atoms 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 binding a particular molecule or interacting with another copy of the same enzyme. How such a variety of inputs can each trigger MST1/2's 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 turned that enzyme on," Kavran says.

In the study, she and her colleagues used test tube and cell culture experiments with human MST2 to show that the myriad upstream activators of this enzyme trigger MST2 autophosphorylation the same way--simply by increasing the local concentration of these enzymes--thus reducing the distance between the enzymatic sites on individual enzymes and making it easier for them to phosphorylate one another.

The researchers believe their discovery is likely to apply not only to MST2 but also its twin MST1 as well as the very similar versions of the enzyme produced in other species.

Although this was principally a basic science study, the results should enhance the ability of researchers to manipulate Hippo pathway signaling, both for basic research as well as for potential therapeutic applications for tissue regeneration and anti-cancer therapies.

"The techniques we used to activate MST2 in cell cultures should be useful to other labs that are studying the Hippo pathway and need a way to turn it on in a controlled manner," Kavran says.

She and her lab plan to investigate how other enzymes in the pathway are regulated.
"Increasing kinase domain proximity promotes MST2 autophosphorylation during Hippo signaling" was written by Thao Tran, Jaba Mitra, Taekjip Ha, and Jennifer Kavran.The research was supported by the National Institutes of Health (R01GM134000, T32CA009110, R35GM122569).

Johns Hopkins University Bloomberg School of Public Health

Related Cell Division Articles from Brightsurf:

Cell division: Cleaning the nucleus without detergents
A team of researchers, spearheaded by the Gerlich lab at IMBA, has uncovered how cells remove unwanted components from the nucleus following mitosis.

Genetic signature boosts protein production during cell division
A research team has uncovered a genetic signature that enables cells to adapt their protein production according to their state.

Inner 'clockwork' sets the time for cell division in bacteria
Researchers at the Biozentrum of the University of Basel have discovered a 'clockwork' mechanism that controls cell division in bacteria.

Scientists detail how chromosomes reorganize after cell division
Researchers have discovered key mechanisms and structural details of a fundamental biological process--how a cell nucleus and its chromosomal material reorganizes itself after cell division.

Targeting cell division in pancreatic cancer
Study provides new evidence of synergistic effects of drugs that inhibit cell division and support for further clinical trials.

Scientists gain new insights into the mechanisms of cell division
Mitosis is the process by which the genetic information encoded on chromosomes is equally distributed to two daughter cells, a fundamental feature of all life on earth.

Cell division at high speed
When two proteins work together, this worsens the prognosis for lung cancer patients: their chances of survival are particularly poor in this case.

Cell biology: The complexity of division by two
Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have identified a novel protein that plays a crucial role in the formation of the mitotic spindle, which is essential for correct segregation of a full set of chromosomes to each daughter cell during cell division.

Better together: Mitochondrial fusion supports cell division
New research from Washington University in St. Louis shows that when cells divide rapidly, their mitochondria are fused together.

Seeing is believing: Monitoring real time changes during cell division
Scientist have cast new light on the behaviour of tiny hair-like structures called cilia found on almost every cell in the body.

Read More: Cell Division News and Cell Division Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to