Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 27, Pages 25605-25611Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M103244200
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Funding
- NCI NIH HHS [CA81398, R01 CA081398] Funding Source: Medline
- NCRR NIH HHS [RR11589, R01 RR011589] Funding Source: Medline
- NHLBI NIH HHS [R01 HL057880] Funding Source: Medline
- NIAID NIH HHS [R01 AI049152, R01 AI032890] Funding Source: Medline
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Human immunodeficiency virus Nef is a small myristylated protein that plays a critical role in AIDS progression. Nef binds with high affinity to the SH3 domain of the myeloid-restricted tyrosine kinase Hck in vitro, identifying this Src-related kinase as a possible cellular target for Nef in macrophages. Here we show that Nef activates endogenous Hck in the granulocyte-macrophage colony-stimulating factor-dependent myeloid cell line, TF-1. Unexpectedly, Nef induced cytokine-independent TF-1 cell outgrowth and constitutive activation of the Stat3 transcription factor. Induction of survival required the Nef SH3 binding and membrane-targeting motifs and was blocked by dominant-negative Stat3 mutants. Nef also stimulated Stat3 activation in primary human macrophages, providing evidence for Stat3 as a Nef effector in a target cell for human immunodeficiency virus.
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