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首页> 外文期刊>Journal of Cell Science >alpha(v)beta3-integrin-dependent activation of focal adhesion kinase mediates NF-kappaB activation and motogenic activity by HIV-1 Tat in endothelial cells.
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alpha(v)beta3-integrin-dependent activation of focal adhesion kinase mediates NF-kappaB activation and motogenic activity by HIV-1 Tat in endothelial cells.

机译：粘着斑激酶的α（v）β3整合素依赖性激活介导了HIV-1 Tat在内皮细胞中的NF-κB激活和运动活性。

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摘要

Once in the extracellular environment, the transactivator protein HIV-1 Tat exerts several pleiotropic effects by interacting with different cellular receptors, including integrin alpha(v)beta3. Real-time surface plasmon resonance analysis reveals that Tat/alpha(V)beta3 interaction occurs with rapid kinetics (association and dissociation rates equal to 1.16 x 10(7) M(-1) s(-1) and 3.78 x 10(-1) s(-1), respectively) and high affinity (dissociation constant = 32 nM). Through this interaction, substratum-immobilized Tat promotes adhesion and motogenic activity in endothelial cells. Also, alpha(v)beta(3)/Tat interaction triggers the activation of focal adhesion kinase, RhoA and pp60src. Overexpression of the dominant negative form of focal adhesion kinase, but not of an inactive Leu1034Ser substitution mutant isoform, impairs the activation of focal adhesion kinase and RhoA, but not that of pp60src, without affecting endothelial cell adhesion and spreading. alpha(v)beta3/Tat interaction triggers the activation of NF-kappaB in endothelial cells in a focal adhesion kinase-, RhoA- and pp60src-dependent manner, as shown in dominant negative focal adhesion kinase transfectants or using specific pharmacological inhibitors. Finally, the activation of focal adhesion kinase, RhoA, NF-kappaB and pp60src are required to mediate the motogenic activity of Tat in endothelial cells. Since Tat accumulates in an immobilized form in the extracellular matrix, these results provide new biochemical and biological insights about alpha(v)beta3/Tat interaction exploitable for the design of anti-Tat strategies.
机译：一旦进入细胞外环境，反式激活蛋白HIV-1 Tat通过与不同的细胞受体（包括整联蛋白alpha（v）beta3）相互作用，发挥多种作用。实时表面等离子体共振分析表明Tat / alpha（V）beta3相互作用发生快速动力学（关联和解离速率等于1.16 x 10（7）M（-1）s（-1）和3.78 x 10（- 1）分别是s（-1）和高亲和力（解离常数= 32 nM）。通过这种相互作用，固定在基质上的Tat促进了内皮细胞的粘附和致突变活性。此外，alpha（v）beta（3）/ Tat相互作用会触发粘着斑激酶，RhoA和pp60src的激活。粘着斑激酶的显性负性形式的过表达，而不是失活的Leu1034Ser替代突变体亚型的过表达，会损害粘着斑激酶和RhoA的激活，而不是pp60src的激活，而不影响内皮细胞的粘着和扩散。 alpha（v）beta3 / Tat相互作用以粘着斑激酶，RhoA和pp60src依赖性方式触发内皮细胞中NF-κB的活化，如显性阴性粘着斑激酶转染子或使用特定的药理抑制剂所示。最后，粘着斑激酶，RhoA，NF-κB和pp60src的激活是介导Tat在内皮细胞中的运动活性所必需的。由于Tat以固定形式积累在细胞外基质中，因此这些结果提供了有关alpha（v）beta3 / Tat相互作用的新生物化学和生物学见解，可用于设计反Tat策略。

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