The p95-100kDa ligand of the T cell-specific adaptor (TSAd) protein Src-homology-2 (SH2) domain implicated in TSAd nuclear import is p97 Valosin-containing protein (VCP)
The p95-100kDa ligand of the T cell-specific adaptor (TSAd) protein Src-homology-2 (SH2) domain implicated in TSAd nuclear import is p97 Valosin-containing protein (VCP)
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DOI：
10.1016/j.imlet.2004.10.021
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发表时间：
2005-03-15
影响因子：
4.4
通讯作者：
King, PD
中科院分区：
文献类型：
--
作者：
Marti, F;King, PD
T细胞特异性衔接蛋白（TSAd）是T细胞中正常T细胞抗原受体（TCR）诱导的细胞因子基因转录所必需的。TSAd如何控制细胞因子转录尚不清楚。以前，我们已经表明，TSAA被积极运输到T细胞的细胞核，这表明该适配器可能在该细胞隔室内部分发挥作用。TSAA的核转位依赖于完整的Src-同源性-2（SH 2）结构域，并且SH 2结构域的p95-100 kDa配体已经涉及核输入。在这里，使用微量化学技术，我们确定p95-100为p97 Valosin-containing蛋白（VCP），其在酵母中的同源物是细胞分裂控制蛋白，CDC 48。TSAd和VCP之间的物理相互作用可以在T细胞中的内源性蛋白质之间证明。相互作用是直接的，并且依赖于VCP的酪氨酸残基805的磷酸化，所述酪氨酸残基805先前被认为是参与TCR信号传导的酪氨酸激酶的主要靶标。值得注意的是，使用CDC 48突变酵母，我们证明VCP/CDC 48是必需的运输TSAd进入真核细胞核。这些发现为TSAd核输入机制和TSAd在T细胞信号转导中的作用提供了重要的见解。(c)2004 Elsevier B. V.保留所有权利。
T cell-specific adapter protein (TSAd) is required for normal T cell antigen receptor (TCR)-induced transcription of cytokine genes in T cells. How TSAd controls cytokine transcription is unknown. Previously, we have shown that TSAA is actively transported to the nucleus of T cells suggesting that this adapter may in part function within this cellular compartment. Nuclear translocation of TSAA is dependent upon an intact Src-homology-2 (SH2) domain and a p95-100 kDa ligand of the SH2 domain has been implicated in nuclear import. Here, using microchemical techniques, we identify p95-100 as p97 Valosin-containing protein (VCP) whose homolog in yeast is the cell division control protein, CDC48. Physical interaction between TSAd and VCP can be demonstrated between endogenous proteins in T cells. Interaction is direct and is dependent upon phosphorylation of tyrosine residue 805 of VCP that has been previously recognized as a major target of tyrosine kinase(s) involved in TCR signaling. Significantly, with the use of CDC48 mutant yeast, we demonstrate that VCP/CDC48 is required for transport of TSAd into the eukaryotic nucleus. These findings provide important insights into the mechanism of TSAd nuclear import and the role of TSAd in T cell signal transduction. (c) 2004 Elsevier B.V. All rights reserved.