The Neurofibromatosis Type 1 Gene Product Neurofibromin Enhances Cell Motility by Regulating Actin Filament Dynamics via the Rho-ROCK-LIMK2-Cofilin Pathway

Neurofibromin is a neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as a GTPase-activating protein and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell...

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Published in:The Journal of biological chemistry 2005-11, Vol.280 (47), p.39524-39533
Main Authors: Ozawa, Tatsuya, Araki, Norie, Yunoue, Shunji, Tokuo, Hiroshi, Feng, Liping, Patrakitkomjorn, Siriporn, Hara, Toshihiro, Ichikawa, Yasuko, Matsumoto, Kunio, Fujii, Kiyotaka, Saya, Hideyuki
Format: Article
Language:English
Subjects:
Actin Depolymerizing Factors - physiology
Actins - chemistry
Actins - physiology
Base Sequence
Cell Line
Cell Movement - physiology
DNA-Binding Proteins - physiology
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
Lim Kinases
Neurofibromatosis 1 - genetics
Neurofibromatosis 1 - physiopathology
Neurofibromin 1 - antagonists & inhibitors
Neurofibromin 1 - chemistry
Neurofibromin 1 - genetics
Neurofibromin 1 - physiology
Phenotype
Protein-Serine-Threonine Kinases - physiology
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
rho GTP-Binding Proteins - physiology
rho-Associated Kinases
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Small Interfering - genetics
Signal Transduction
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Summary:Neurofibromin is a neurofibromatosis type 1 (NF1) tumor suppressor gene product with a domain that acts as a GTPase-activating protein and functions, in part, as a negative regulator of Ras. Loss of neurofibromin expression in NF1 patients is associated with elevated Ras activity and increased cell proliferation, predisposing to a variety of tumors of the peripheral and central nervous systems. We show here, using the small interfering RNA (siRNA) technique, that neurofibromin dynamically regulates actin cytoskeletal reorganization, followed by enhanced cell motility and gross cell aggregation in Matrigel matrix. NF1 siRNA induces characteristic morphological changes, such as excessive actin stress fiber formation, with elevated negative phosphorylation levels of cofilin, which regulates actin cytoskeletal reorganization by depolymerizing and severing actin filaments. We found that the elevated phosphorylation of cofilin in neurofibromin-depleted cells is promoted by activation of a Rho-ROCK-LIMK2 pathway, which requires Ras activation but is not transduced through three major Ras-mediated downstream pathways via Raf, phosphatidylinositol 3-kinase, and RalGEF. In addition, the exogenous expression of the NF1-GTPase-activating protein-related domain suppressed the NF1 siRNA-induced phenotypes. Neurofibromin was demonstrated to play a significant role in the machinery regulating cell proliferation and in actin cytoskeletal reorganization, which affects cell motility and adhesion. These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M503707200