Abstract
A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p21-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Apoptosis
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Carrier Proteins / physiology*
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Cell Line
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Gene Products, nef / physiology*
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Genes, nef
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HIV-1 / genetics
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HIV-1 / pathogenicity
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HIV-1 / physiology*
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Humans
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Mice
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Mutation
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Signal Transduction
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Transfection
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Virus Replication
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bcl-Associated Death Protein
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nef Gene Products, Human Immunodeficiency Virus
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p21-Activated Kinases
Substances
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BAD protein, human
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Bad protein, mouse
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Carrier Proteins
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Gene Products, nef
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Proto-Oncogene Proteins
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bcl-Associated Death Protein
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nef Gene Products, Human Immunodeficiency Virus
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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p21-Activated Kinases