A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by alsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death

Kohsuke Kanekura, Yuichi Hashimoto, Yoshiko Kita, Jumpei Sasabe, Sadakazu Aiso, Ikuo Nishimoto, Masaaki Matsuoka

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide disimutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overespression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.

Original languageEnglish
Pages (from-to)4532-4543
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number6
DOIs
Publication statusPublished - 2005 Feb 11
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Cell death
Guanine Nucleotides
Genes
Monomeric GTP-Binding Proteins
Guanosine Triphosphate
Superoxides
Small Interfering RNA
Superoxide Dismutase
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by alsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death. / Kanekura, Kohsuke; Hashimoto, Yuichi; Kita, Yoshiko; Sasabe, Jumpei; Aiso, Sadakazu; Nishimoto, Ikuo; Matsuoka, Masaaki.

In: Journal of Biological Chemistry, Vol. 280, No. 6, 11.02.2005, p. 4532-4543.

Research output: Contribution to journalArticle

@article{4d53336373854731a9175facec6f8c9f,
title = "A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by alsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death",
abstract = "AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide disimutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overespression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.",
author = "Kohsuke Kanekura and Yuichi Hashimoto and Yoshiko Kita and Jumpei Sasabe and Sadakazu Aiso and Ikuo Nishimoto and Masaaki Matsuoka",
year = "2005",
month = "2",
day = "11",
doi = "10.1074/jbc.M410508200",
language = "English",
volume = "280",
pages = "4532--4543",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - A Rac1/phosphatidylinositol 3-kinase/Akt3 anti-apoptotic pathway, triggered by alsinLF, the product of the ALS2 gene, antagonizes Cu/Zn-superoxide dismutase (SOD1) mutant-induced motoneuronal cell death

AU - Kanekura, Kohsuke

AU - Hashimoto, Yuichi

AU - Kita, Yoshiko

AU - Sasabe, Jumpei

AU - Aiso, Sadakazu

AU - Nishimoto, Ikuo

AU - Matsuoka, Masaaki

PY - 2005/2/11

Y1 - 2005/2/11

N2 - AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide disimutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overespression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.

AB - AlsinLF, the product of the ALS2 gene, inhibits Cu/Zn-superoxide disimutase (SOD1) mutant-induced neurotoxicity via its Rho guanine nucleotide-exchanging factor domain. We here identified Rac1, a Rho family small GTPase, as a target for the Rho guanine nucleotide-exchanging factor activity of alsinLF. Rac1 associates with alsinLF. The amount of the GTP form of Rac1 is up-regulated by enforced overespression of alsinLF. We further found not only that constitutively active Rac1 suppresses motoneuronal cell death induced by SOD1 mutants but also that the neuroprotective activity of alsinLF was completely inhibited by knocking down the endogenous Rac1 expression with small interfering RNA for Rac1, indicating that Rac1 is the major effector for alsinLF-mediated neuroprotection. Such alsinLF/Rac1-mediated neuroprotection occurs specifically against the SOD1 mutant-induced cell death but not against the cell death induced by any other neurotoxic insults in motoneuronal NSC34 cells. We further demonstrated that the alsinLF/Rac1-mediated neuroprotective signal is transmitted to the phosphatidylinositol 3-kinase/Akt anti-apoptotic axis. Among three Akt family proteins, Akt3 is the major downstream mediator for alsinLF/Rac1-mediated neuroprotection, which is specifically effective against SOD1 mutant-induced neurotoxicity.

UR - http://www.scopus.com/inward/record.url?scp=14244264186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14244264186&partnerID=8YFLogxK

U2 - 10.1074/jbc.M410508200

DO - 10.1074/jbc.M410508200

M3 - Article

C2 - 15579468

AN - SCOPUS:14244264186

VL - 280

SP - 4532

EP - 4543

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -