title: MEK1 is required for PTEN membrane recruitment, AKT regulation, and the maintenance of peripheral tolerance.
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.
authors: Department of Microbiology and Immunobiology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors: Katarina
authors: K
authors: Zmajkovicova
authors: Veronika
authors: V
authors: Jesenberger
authors: Federica
authors: F
authors: Catalanotti
authors: Christian
authors: C
authors: Baumgartner
authors: Gloria
authors: G
authors: Reyes
authors: Manuela
authors: M
authors: Baccarini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D019556:COS Cells; D015815:Cell Adhesion Molecules; D016923:Cell Death; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D005838:Genotype; D051528:Guanylate Kinases; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010641:Phenotype; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D017634:Self Tolerance; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D018129:Phosphatidylinositol Phosphates; D047428:Protein Kinase Inhibitors; C055525:phosphatidylinositol 3-phosphate; D014443:Tyrosine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D051528:Guanylate Kinases; C493280:Magi1 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse