The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway

Tatsuya Ozawa, Norie Araki, Shunji Yunoue, Hiroshi Tokuo, Liping Feng, Siriporn Patrakitkomjorn, Toshihiro Hara, Yasuko Ichikawa, Kunio Matsumoto, Kiyotaka Fuji, Hideyuki Saya

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Abstract

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.

Original languageEnglish
Pages (from-to)39524-39533
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number47
DOIs
Publication statusPublished - 2005 Nov 25
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ozawa, T., Araki, N., Yunoue, S., Tokuo, H., Feng, L., Patrakitkomjorn, S., Hara, T., Ichikawa, Y., Matsumoto, K., Fuji, K., & Saya, H. (2005). The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway. Journal of Biological Chemistry, 280(47), 39524-39533. https://doi.org/10.1074/jbc.M503707200