MEK1 Mediates PTEN Recruitment to the Plasma Membrane Free

Much effort has been directed toward development of inhibitors of the RAF/mitogenactivated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) pathway, a major downstream effector of oncogenic RAS signaling that is deregulated in cancer. A better understanding of interactions between the RAF/MEK/ERK pathway and other RAS effector pathways in cancer could provide insight into how feedback mechanisms contribute to drug resistance. Given previous evidence of cross-talk between the RAF/MEK/ERK and phosphatidylinositide-3 kinase (PI3K)/AKT pathways, Zmajkovicova and colleagues evaluated the effect of MEK1 loss on AKT activation in mouse embryonic fibroblasts and found that AKT phosphorylation was markedly increased in MEK1-deficient cells. MEK1 loss also led to a significant reduction in membrane-associated levels of the tumor suppressor PTEN, which dephosphorylates phosphatidylinositol 3,4,5 triphosphate to prevent AKT membrane recruitment and subsequent activation. Furthermore, conditional deletion of Mek1 in vivo caused phenotypes such as myeloproliferation and a lupus-like autoimmune disorder that were similar to those seen in Pten-deficient mice and constitutively active Akt transgenic mice. MEK1 did not directly bind PTEN but was required for recruitment of membrane-associated guanylate kinase, WW and PDZ domain containing 1 (MAGI1), a scaffolding protein that directly binds PTEN, and formation of a MEK1–MAGI1–PTEN ternary complex at the plasma membrane. Importantly, negative feedback phosphorylation of MEK1 by ERK, its downstream target, was required for formation of the MEK1–MAGI1–PTEN complex, providing a potential mechanistic explanation for why PI3K pathway activation is frequently observed in cells treated with MEK inhibitors and support for combined inhibition of these pathways to prevent release of negative feedback mechanisms in cancer cells.

Zmajkovicova K, Jesenberger V, Catalanotti F, Baumgartner C, Reyes G, Baccarini M. MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance. Mol Cell 2013 Feb 28 [Epub ahead of print].

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