HIV-1 tat activates dual nox pathways leading to independent activation of ERK and JNK MAP kinases

Feng Wu Ru, Zhenyi Ma, David P. Myers, Lance S. Terada

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Human immunodeficiency virus, type 1 Tat is known to exert pleiotropic effects on the vascular endothelium through mitogen-activated protein (MAP) kinases, although the signaling pathways leading to MAP kinase activation are incompletely understood. We focused on proximal pathways potentially governing downstream MAP kinase activity by Tat. Within 2 min, Tat activated both Ras and Rho GTPases in endothelial cells, leading to ERK phosphorylation by 10 min. Notably, Rac1 was necessary for downstream activation of RhoA and both Rac1 and RhoA acted upstream of the Ras/ERK cassette. Antioxidants and the oxidase inhibitor diphenylene iodonium blocked ERK phosphorylation, but specific interference with the canonical Nox2 oxidase had no effect on ERK. Instead, knock down of the novel oxidase Nox4 completely suppressed Tat-dependent Ras and ERK activation downstream of Rac1 and RhoA. Conversely, interference with Rac1, PAK1, and Nox2 blocked JNK phosphorylation, whereas RhoA(N19) and Nox4 knock down did not. Further, knock down of Nox2, but not Nox4, blocked Tat-induced cytoskeletal rearrangement, whereas knock down of Nox4, but not Nox2, blocked Tat-dependent proliferation. Rac1, therefore, bifurcates Tat signaling, leading to concurrent but separate Nox4-dependent Ras/ERK activation, and Nox2-dependent JNK activation. Tat signaling, therefore, provides an example of Nox-specific differential control of MAP kinase pathways.

Original languageEnglish (US)
Pages (from-to)37412-37419
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number52
DOIs
StatePublished - Dec 28 2007

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JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
HIV-1
Chemical activation
Phosphorylation
Oxidoreductases
ras Proteins
rho GTP-Binding Proteins
Vascular Endothelium
Endothelial cells
Viruses
Endothelial Cells
Antioxidants

ASJC Scopus subject areas

  • Biochemistry

Cite this

HIV-1 tat activates dual nox pathways leading to independent activation of ERK and JNK MAP kinases. / Ru, Feng Wu; Ma, Zhenyi; Myers, David P.; Terada, Lance S.

In: Journal of Biological Chemistry, Vol. 282, No. 52, 28.12.2007, p. 37412-37419.

Research output: Contribution to journalArticle

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AU - Ma, Zhenyi

AU - Myers, David P.

AU - Terada, Lance S.

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AB - Human immunodeficiency virus, type 1 Tat is known to exert pleiotropic effects on the vascular endothelium through mitogen-activated protein (MAP) kinases, although the signaling pathways leading to MAP kinase activation are incompletely understood. We focused on proximal pathways potentially governing downstream MAP kinase activity by Tat. Within 2 min, Tat activated both Ras and Rho GTPases in endothelial cells, leading to ERK phosphorylation by 10 min. Notably, Rac1 was necessary for downstream activation of RhoA and both Rac1 and RhoA acted upstream of the Ras/ERK cassette. Antioxidants and the oxidase inhibitor diphenylene iodonium blocked ERK phosphorylation, but specific interference with the canonical Nox2 oxidase had no effect on ERK. Instead, knock down of the novel oxidase Nox4 completely suppressed Tat-dependent Ras and ERK activation downstream of Rac1 and RhoA. Conversely, interference with Rac1, PAK1, and Nox2 blocked JNK phosphorylation, whereas RhoA(N19) and Nox4 knock down did not. Further, knock down of Nox2, but not Nox4, blocked Tat-induced cytoskeletal rearrangement, whereas knock down of Nox4, but not Nox2, blocked Tat-dependent proliferation. Rac1, therefore, bifurcates Tat signaling, leading to concurrent but separate Nox4-dependent Ras/ERK activation, and Nox2-dependent JNK activation. Tat signaling, therefore, provides an example of Nox-specific differential control of MAP kinase pathways.

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