The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B.
The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B.
复制标题
X 连锁淋巴增殖综合征基因产物 SH2D1A 与 p62dok (Dok1) 结合并激活 NF-kappa B。
DOI：
10.1073/pnas.130193097
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发表时间：
2000
影响因子：
11.1
通讯作者：
Kieff,E
中科院分区：
文献类型：
--
作者：
Sylla,BS;Murphy,K;Cahir-McFarland,E;Lane,WS;Mosialos,G;Kieff,E
X连锁淋巴组织增生综合征（XLP）是一种遗传性疾病，其中受影响的男性对爱泼斯坦-巴尔病毒感染有病态或致命的反应。XLP缺陷已被映射到编码128个残基的蛋白质SH 2D 1A的基因，该蛋白质主要由Src同源2（SH 2）结构域组成。我们现在报告SH 2D 1A与Dok 1相关，Dok 1是一种与Ras-GAP，Csk和Nck相互作用的蛋白质。在XLP中鉴定的SH 2 D1 A SH 2结构域突变体与Dok 1不相关，这与这种相互作用与XLP相关的假设雅阁。SH 2D 1A与Dok 1的结合也依赖于Dok 1 Y 449在序列SQVQK中的磷酸化。此外，发现SH 2D 1A的过表达在293 T细胞中激活NF-κB。NF-κB被SH 2 D1 A激活不依赖于野生型SH 2结构域，并被显性负性IκB激酶β抑制。因此，SH 2D 1A可以影响多种细胞内信号传导途径，这些途径在正常有效的宿主对EB病毒感染的反应中可能是重要的。
The X-linked lymphoproliferative syndrome (XLP) is a genetic disorder in which affected males have a morbid or fatal response to Epstein–Barr virus infection. The XLP deficiency has been mapped to a gene encoding a 128-residue protein, SH2D1A, which is comprised principally of a Src homology 2 (SH2) domain. We now report that SH2D1A associates with Dok1, a protein that interacts with Ras-GAP, Csk, and Nck. An SH2D1A SH2 domain mutant that has been identified in XLP does not associate with Dok1, in accord with the hypothesis that this interaction is linked to XLP. The association of SH2D1A with Dok1 also depends on phosphorylation of Dok1 Y449in the sequence ALYSQVQK. Further, overexpression of SH2D1A is found to activate NF-κB in 293T cells. NF-κB activation by SH2D1A does not depend on the wild-type SH2 domain and is inhibited by a dominant-negative IκB kinase β. Thus, SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein–Barr virus infection.