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The Raf/MEK/ERK and PI3K/Akt pathways are prominent effectors of oncogenic Ras. These pathways negatively regulate each other, but the mechanism involved is incompletely understood. We now identify MEK1 as an essential regulator of lipid/protein phosphatase PTEN, through which it controls phosphatidylinositol-3-phosphate accumulation and AKT signaling. MEK1 ablation stabilizes AKT activation and, in vivo, causes a lupus-like autoimmune disease and myeloproliferation. Mechanistically, MEK1 is necessary for PTEN membrane recruitment as part of a ternary complex containing the multidomain adaptor MAGI1. Complex formation is independent of MEK1 kinase activity but requires phosphorylation of T292 on MEK1 by activated ERK. Thus, inhibiting the ERK pathway reduces PTEN membrane recruitment, increasing phosphatidylinositol-3-phosphate accumulation and AKT activation. Our data offer a conceptual framework for the observation that activation of the PI3K pathway frequently mediate resistance to MEK inhibitors and for the promising results obtained by combined MEK/PI3K inhibition in preclinical cancer models.
Junge Autofahrer in ArRiyadh
(2013)
A Novel and Automated Circle Pattern Recognition Technique for Infra-Red Stero Camera Calibration
(2013)
Large scale integration and evaluation of aal technologies in eastern austria - the modulaar project
(2013)
Surface Electromyography Measurements of Dorsal Muscle Cross-Activation in Therapeutic Climbing
(2013)
Bioreactor and scaffold design for the mechanical stimulation of anterior cruciate ligament grafts
(2013)