Molecular Cell
Volume 50, Issue 1, 11 April 2013, Pages 43-55
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Article
MEK1 Is Required for PTEN Membrane Recruitment, AKT Regulation, and the Maintenance of Peripheral Tolerance

https://doi.org/10.1016/j.molcel.2013.01.037Get rights and content
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Summary

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.

Highlights

► A complex of MEK1, MAGI1, and PTEN regulates PIP3 turnover and AKT signaling ► Ablation/inhibition of MEK1 blocks complex formation and PTEN membrane recruitment ► ERK-mediated MEK1 phosphorylation coordinates the timing of ERK and AKT signaling ► In vivo, MEK1 ablation induces AKT activation and a breach in peripheral tolerance

Cited by (0)

2

Present address: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA

3

Present address: Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, Department 0636, La Jolla, CA 92093-0636, USA

4

These authors contributed equally to this work