Rewiring MAP kinases in Saccharomyces cerevisiae to regulate novel targets through ubiquitination.

Nature has evolved a number of ways to link signals from a cell’s environment, like the concentration of a hormone, to the behavior of that cell. These new connections often form by reusing certain common signaling components, such as mitogen-activated protein kinases. These enzymes – referred to as MAPKs for short – are activated by specific signals and alter the activity of target proteins in the cell by adding a phosphate group to them: a process called phosphorylation. These connections thus dictate how cells respond to their environments – and consequently, disruptions to the connections are a common source of disease. Groves, Khakhar et al. set out to understand how connections can be made between a MAPK and a new target protein to gain insights into how these links emerge through evolution and how they might break in disease. Their approach focused on one of the ways that phosphorylation can alter the activity of a target protein: marking it for degradation. Experiments with budding yeast showed that a MAPK could only achieve this if two conditions are met. First, the target protein and kinase need to bind to each other. Second, the target needs to contain a site that when phosphorylated is subsequently recognized by the cell’s protein degradation machinery. By engineering proteins so that they fulfilled these two criteria, Groves, Khakhar et al. created new connections between a yeast MAPK called Fus3 or a human MAPK called ERK2 and a variety of targets. The results showed that the parts of the proteins involved in the interaction step could be completely separate from the parts that are involved in the phosphorylation step. This suggests that connections between kinases and their targets can be rewired simple by mixing together parts of other existing proteins. Finally, Groves, Khakhar et al. confirmed that engineered connections between kinases and targets could predictably change how yeast cells responded to a hormone that normally controls the yeast’s reproductive cycle. Together these results bring us one step closer to understanding how cells assemble the signaling pathways that they use to process information. However further work is needed to see if these findings can be generalized to other signaling components, and if so, to explore if new connections can be built to yield more complicated cellular behaviors.