Abstract
Neurofibromin contains several domains, most notably a GAP-related domain (GRD), that down-regulates Ras pathways. The functions of the non-GRD neurofibromin domains are largely known. Here we show that the pre-GRD region of neurofibromin alters the expression of genes involved in cell adhesion and migration and acts as a negative regulator of the Rac1/Pak1/LIMK1/cofilin pathway. Thus, neurofibromin-deficient glioblastoma and mouse fibroblasts are enriched in Rac1-GTP, p-Pak1, p-LIMK1 and p-cofilin, with all proteins exhibiting decreased expression upon expression of NF1(1-1163) polypeptide. Concomitantly, actin stress fibers and focal adhesion were disassembled and cell migration was halted. These effects were independent of the Ras signaling pathways. It seems that NF1(1-1163), through negative regulation of Rac-1, shifts the balance from a state of inactive phospho-cofilin to active unphosphorylated cofilin, resulting in severing of F-actin. Impairment of these cellular functions of neurofibromin provides novel insights into the invasiveness/progression of NF1-associated tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Depolymerizing Factors / genetics
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Actin Depolymerizing Factors / metabolism*
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Animals
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Cell Line
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Cell Movement / physiology*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Focal Adhesions / metabolism
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Gene Expression Profiling
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Gene Expression Regulation
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Glioblastoma / metabolism
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Humans
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Lim Kinases / genetics
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Lim Kinases / metabolism*
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Mice
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Mice, Knockout
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Neurofibromin 1 / genetics
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Neurofibromin 1 / metabolism*
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Oligonucleotide Array Sequence Analysis
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology*
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p21-Activated Kinases / genetics
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p21-Activated Kinases / metabolism
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
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ras Proteins / genetics
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ras Proteins / metabolism
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism
Substances
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Actin Depolymerizing Factors
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Neurofibromin 1
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Recombinant Fusion Proteins
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Lim Kinases
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Pak1 protein, mouse
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p21-Activated Kinases
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rac1 GTP-Binding Protein
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ras Proteins
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rhoA GTP-Binding Protein