Abstract：
: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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Zmajkovicova K,Jesenberger V,Catalanotti F,Baumgartner C,Reyes G,Baccarini Mdoi
10.1016/j.molcel.2013.01.037subject
Has Abstractpub_date
2013-04-11 00:00:00pages
43-55issue
1eissn
1097-2765issn
1097-4164pii
S1097-2765(13)00101-9journal_volume
50pub_type
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