Mechanism behind MST2 Autophosphorylation in Hippo Pathway Revealed

Researchers at the Johns Hopkins Bloomberg School of Public Health have delved into the workings of the Hippo pathway and discovered how one of its core components, an enzyme called MST2, can be activated by multiple signaling inputs. Their discovery was reported today 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 senior author Jennifer Kavran.

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.

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 the study, the team was able 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.