AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation
AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation
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DOI：
10.1074/jbc.m407617200
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发表时间：
2004-10-22
影响因子：
4.8
通讯作者：
Min, W
中科院分区：
文献类型：
--
作者：
Zhang, HF;Zhang, R;Min, W
以前，我们已经表明，ASK相互作用蛋白1（AIP 1，也称为DAB 2 IP），一个新的成员的Ras-GAP蛋白家族，介导TNF诱导的激活ASK 1-JNK信号通路。然而，TNF信号传导与AIP 1偶联的机制尚不清楚。在这里，我们表明，AIP 1定位于质膜上的静息内皮细胞（EC）与TNFR 1的复合物。TNF结合诱导AIP 1从TNFR 1释放，导致细胞质易位和伴随的由TRADD、RIP 1、TRAF 2和AIP 1组成的细胞内信号传导复合物的形成。富含脯氨酸的区域（氨基酸796 - 807）对于维持AIP 1处于闭合形式是关键的，其与TNFR 1的不同于死亡结构域的区域（TNFR 1与TRADD结合的位点）结合。缺失该富含脯氨酸区域的AIP 1突变体组成型结合TRAF 2和ASK 1。AIP 1的PERIOD样结构域（氨基酸591 - 719）结合TRAF 2的完整RING指，并特异性增强TRAF 2诱导的ASK 1活化。同时，AIP 1与TRAF 2的结合抑制TNF诱导的IKK-NF-kappaB信号传导。总之，我们的数据表明，AIP 1是一种新的转换器在TNF诱导的TRAF 2依赖性激活ASK 1，介导JNK与NF-κ B信号之间的平衡。
Previously we have shown that ASK-interacting protein 1 (AIP1, also known as DAB2IP), a novel member of the Ras-GAP protein family, mediates TNF-induced activation of ASK1-JNK signaling pathway. However, the mechanism by which TNF signaling is coupled to AIP1 is not known. Here we show that AIP1 is localized on the plasma membrane in resting endothelial cells (EC) in a complex with TNFR1. TNF binding induces release of AIP1 from TNFR1, resulting in cytoplasmic translocation and concomitant formation of an intracellular signaling complex comprised of TRADD, RIP1, TRAF2, and AIPl. A proline-rich region ( amino acids 796 - 807) is critical for maintaining AIP1 in a closed form, which associates with a region of TNFR1 distinct from the death domain, the site of TNFR1 association with TRADD. An AIP1 mutant with deletion of this proline-rich region constitutively binds to TRAF2 and ASK1. A PERIOD-like domain ( amino acids 591 - 719) of AIP1 binds to the intact RING finger of TRAF2, and specifically enhances TRAF2-induced ASK1 activation. At the same time, the binding of AIP1 to TRAF2 inhibits TNF-induced IKK-NF-kappaB signaling. Taken together, our data suggest that AIP1 is a novel transducer in TNF-induced TRAF2-dependent activation of ASK1 that mediates a balance between JNK versus NF-kappaB signaling.