Cells have to sense and react to environmental stimuli
Our body is made up of billions of cells that need to sense environmental signals and react to them in a coordinated response. Sensing of signals occurs via receptors on the surface of each cell that then trigger specific signal transduction cascades within the cell. These in turn regulate cell proliferation and division, but also initiate the fight against bacterial or viral infections. The ERK pathway, for example, involves the consecutive activation of RAS, RAF, MEK and ERK proteins, ultimately regulation embryonic development, cell differentiation and proliferation, as well as programmed cell death.
MEK1 balances signaling cascades that control cell proliferation
The protein MEK exists in two isoforms, MEK1 and MEK2, which form a complex in cells. A few years ago, the Baccarini lab showed that if MEK1 is ablated, MEK2 cannot be turned off and the MAP-kinase pathway is constitutively active, leading to hyperproliferation of cells. To inactivate the MEK1/2 complex and hence the signaling cascade, MEK1 has to be modified at a critical residue through active ERK.
Baccarini, who led the study as part of the doctoral program “Molecular mechanisms of cell signaling”, says: “Our new finding show that modified MEK1 is also crucial to downregulate signaling through the PI3K/AKT pathway, a signaling cascade that regulates cell proliferation and survival.” In this case, modified MEK1 binds to PTEN, leading to its translocation to the plasma membrane, where it stops the production of the signaling molecule PIP3. “In this way, MEK1 balances signaling through two cascade that regulate cell proliferation and survival. If MEK1 is ablated, both the ERK and the PI3K/AKT pathway are constitutively active resulting in hyperproliferation”, Baccarini explain.
Cue for “personalized medicine”
This crucial role of MEK1 also explains how resistance to treatment with inhibitors of the ERK pathway emerges. Baccarini says: “Tumors treated with ERK pathway inhibitors don’t produce any modified MEK1 that could turn off PI3K/AKT signaling. This facilitates the emergence of resistance mechanisms mediated by the PI3K pathway.”
The findings of the study therefore give cues to “personalized medicine”, an individualized treatment approach. Because inhibition of the ERK pathway in tumors with functional PTEN can cause hyperactivation of the PI3K/AKT pathway, these patients should receive additional treatment with PI3K/AKT inhibitors. “Our results show that cellular signaling pathways cannot be studied in isolation, but need to be seen as the complex network they are. Only when we understand the links within this network, will we be able to optimize therapeutic strategies to provide patients with the most effective treatment and the least side effects”, concludes Baccarini.
Original publication in Molecular Cell
Katarina Zmajkovicova, Veronika Jesenberger, Federica Catalanotti, Christian Baumgartner, Gloria Reyes, and Manuela Baccarini: MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance. In: Molecular Cell (2013).