Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras

Shunji Yunoue, Hiroshi Tokuo, Kohji Fukunaga, Liping Feng, Tatsuya Ozawa, Toru Nishi, Akira Kikuchi, Seisuke Hattori, Junichi Kuratsu, Hideyuki Saya, Norie Araki

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominant-negative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.

Original languageEnglish
Pages (from-to)26958-26969
Number of pages12
JournalJournal of Biological Chemistry
Volume278
Issue number29
DOIs
Publication statusPublished - 2003 Jul 18
Externally publishedYes

Fingerprint

Neurofibromin 1
GTPase-Activating Proteins
Neurofibromatosis 1
Tumors
Nerve Growth Factor
Neoplasms
ras GTPase-Activating Proteins
PC12 Cells
Neurites
Alternative Splicing
Neurons
Rats
Elongation
Chemical activation
Learning Disorders
Data storage equipment
Down-Regulation
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. / Yunoue, Shunji; Tokuo, Hiroshi; Fukunaga, Kohji; Feng, Liping; Ozawa, Tatsuya; Nishi, Toru; Kikuchi, Akira; Hattori, Seisuke; Kuratsu, Junichi; Saya, Hideyuki; Araki, Norie.

In: Journal of Biological Chemistry, Vol. 278, No. 29, 18.07.2003, p. 26958-26969.

Research output: Contribution to journalArticle

Yunoue, S, Tokuo, H, Fukunaga, K, Feng, L, Ozawa, T, Nishi, T, Kikuchi, A, Hattori, S, Kuratsu, J, Saya, H & Araki, N 2003, 'Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras', Journal of Biological Chemistry, vol. 278, no. 29, pp. 26958-26969. https://doi.org/10.1074/jbc.M209413200
Yunoue, Shunji ; Tokuo, Hiroshi ; Fukunaga, Kohji ; Feng, Liping ; Ozawa, Tatsuya ; Nishi, Toru ; Kikuchi, Akira ; Hattori, Seisuke ; Kuratsu, Junichi ; Saya, Hideyuki ; Araki, Norie. / Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 29. pp. 26958-26969.
@article{af687a2b408948709a34c77d91f7c1aa,
title = "Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras",
abstract = "Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominant-negative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.",
author = "Shunji Yunoue and Hiroshi Tokuo and Kohji Fukunaga and Liping Feng and Tatsuya Ozawa and Toru Nishi and Akira Kikuchi and Seisuke Hattori and Junichi Kuratsu and Hideyuki Saya and Norie Araki",
year = "2003",
month = "7",
day = "18",
doi = "10.1074/jbc.M209413200",
language = "English",
volume = "278",
pages = "26958--26969",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "29",

}

TY - JOUR

T1 - Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras

AU - Yunoue, Shunji

AU - Tokuo, Hiroshi

AU - Fukunaga, Kohji

AU - Feng, Liping

AU - Ozawa, Tatsuya

AU - Nishi, Toru

AU - Kikuchi, Akira

AU - Hattori, Seisuke

AU - Kuratsu, Junichi

AU - Saya, Hideyuki

AU - Araki, Norie

PY - 2003/7/18

Y1 - 2003/7/18

N2 - Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominant-negative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.

AB - Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominant-negative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.

UR - http://www.scopus.com/inward/record.url?scp=0038711739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038711739&partnerID=8YFLogxK

U2 - 10.1074/jbc.M209413200

DO - 10.1074/jbc.M209413200

M3 - Article

VL - 278

SP - 26958

EP - 26969

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 29

ER -