Abstract
Neurofibromatosis 2 (NF2) is a tumor suppressor, although the molecular mechanism accounting for this effect remains unknown. Here, we show that merlin exerts its activity by inhibiting phosphatidylinositol 3-kinase (PI3-kinase), through binding to PIKE-L. Wild-type merlin, but not patient-derived mutant (L64P), binds PIKE-L and inhibits PI3-kinase activity. This suppression of PI3-kinase activity results from merlin disrupting the binding of PIKE-L to PI3-kinase. In addition, merlin suppression of PI3-kinase activity as well as schwannoma cell growth is abrogated by a single PIKE-L point mutation (P187L) that cannot bind merlin but can still activate PI3-kinase. Knocking down PIKE-L with RNA interference abolishes merlin's tumor-suppressive activity. Our data support the hypothesis that PIKE-L is an important mediator of merlin growth suppression.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Animals
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Cell Line
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Cell Proliferation
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Coloring Agents / pharmacology
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GTP-Binding Proteins / metabolism*
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GTPase-Activating Proteins / metabolism*
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Glutathione Transferase / metabolism
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Humans
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Immunoprecipitation
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Leucine / chemistry
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Microscopy, Fluorescence
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Mutation
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Neurilemmoma / metabolism
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Neurofibromatosis 2 / metabolism*
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Neurofibromin 2 / metabolism
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Neurofibromin 2 / physiology*
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Phosphatidylinositol 3-Kinases / metabolism*
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Point Mutation
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Protein Binding
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RNA Interference
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Rats
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Subcellular Fractions
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Tetrazolium Salts / pharmacology
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Thiazoles / pharmacology
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Time Factors
Substances
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Coloring Agents
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GTPase-Activating Proteins
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Neurofibromin 2
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Tetrazolium Salts
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Thiazoles
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Glutathione Transferase
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Phosphatidylinositol 3-Kinases
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AGAP2 protein, human
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GTP-Binding Proteins
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thiazolyl blue
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Leucine