Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling
Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling
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DOI：
10.1074/jbc.m111423200
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发表时间：
2002-03-08
影响因子：
4.8
通讯作者：
Vadas, MA
中科院分区：
文献类型：
--
作者：
Xia, P;Wang, LJ;Vadas, MA
肿瘤坏死因子-α受体相关因子2(TRAF2)是肿瘤坏死因子受体超家族的主要介体之一，通过激活核因子-kappaB、JNK、抗细胞凋亡等途径将肿瘤坏死因子信号传导至多种功能靶点。我们研究了TRAF2如何以不同的方式调节不同的下游信号。我们现在报告了一种新的TRAF2介导的信号转导机制，这种机制是通过TRAF2与鞘氨醇激酶(SphK)的关联来揭示的，SphK是一种负责产生鞘氨醇1-磷酸的脂蛋白激酶。我们鉴定了一个TRAF2结合基序的SphK，它介导了TRAF2和SphK之间的相互作用，导致了酶的激活，而这是TRAF2介导的NF-kappaB而不是JNK激活所必需的。此外，通过使用一个激酶失活的显性负性SphK和一个缺乏TRAF2结合基序的突变体SphK，我们证明了TRAF2与SphK的相互作用以及随后的SphK激活对于防止肿瘤坏死因子刺激下的细胞凋亡至关重要。这些发现表明，SphK在TRAF2特异性激活核因子-kappaB和抗细胞凋亡的信号转导中发挥作用。
Tumor necrosis factor-alpha (TNF) receptor-associated factor 2 (TRAF2) is one of the major mediators of TNF receptor superfamily transducing TNF signaling to various functional targets, including activation of NF-kappaB, JNK, and antiapoptosis. We investigated how TRAF2 mediates differentially the distinct downstream signals. We now report a novel mechanism of TRAF2-mediated signal transduction revealed by an association of TRAF2 with sphingosine kinase (SphK), a lipid kinase that is responsible for the production of sphingosine 1-phosphate. We identified a TRAF2-binding motif of SphK that mediated the interaction between TRAF2 and SphK resulting in the activation of the enzyme, which in turn is required for TRAF2-mediated activation of NF-kappaB but not JNK In addition, by using a kinase inactive dominant-negative SphK and a mutant SphK that lacks TRAF2-binding motif we show that the interaction of TRAF2 with SphK and subsequent activation of SphK are critical for prevention of apoptosis during TNF stimulation. These findings show a role for SphK in the signal transduction by TRAF2 specifically leading to activation of NF-kappaB and antiapoptosis.