Dok-4 Is a Novel Negative Regulator of T Cell Activation
Dok-4 Is a Novel Negative Regulator of T Cell Activation
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DOI：
10.4049/jimmunol.0802203
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发表时间：
2009-06-15
影响因子：
4.4
通讯作者：
Nunes, Jacques A.
中科院分区：
文献类型：
--
作者：
Gerard, Audrey;Ghiotto, Marguerite;Nunes, Jacques A.
Dok-4（酪氨酸激酶 4 的下游）是最近鉴定的接头蛋白 Dok 家族的成员，其特征在于氨基末端普莱克斯特林同源结构域、磷酸酪氨酸结合结构域以及含有多个酪氨酸和富含聚脯氨酸基序的羧基末端区域。 Dok 家族的两个成员 Dok-1 和 Dok-2 已被描述为 T 细胞中的负调节因子。然而，Dok-4（也在 T 细胞中表达）的功能仍不清楚。在这项研究中，我们报道了 Dok-4 在 TCR 参与后被磷酸化，并在 T 细胞的细胞质内穿梭，然后在免疫突触形成后被招募到极化微管组织中心。使用 RNA 干扰构建体进行的功能丧失实验表明，Dok-4 是 ERK 磷酸化、IL-2 启动子活性和 T 细胞增殖的负调节因子。野生型 Dok-4 的外源表达会诱导 Rap1 的显着激活，从而参与 ERK 的调节。 Dok-4 的 pleckstrin 同源结构域是其细胞质穿梭和重新定位及其对 T 细胞激活的抑制特性所必需的。因此，Dok-4 代表了一种新型的 T 细胞负调节因子。免疫学杂志，2009，182：7681-7689。
Dok-4 (downstream of tyrosine kinase-4) is a recently identified member of the Dok family of adaptor proteins, which are characterized by an amino-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and a carboxyl-terminal region containing several tyrosines and poly-proline-rich motif's. Two members of the Dok family, Dok-1 and Dok-2, have already been described as negative regulators in T cells. However, the function of Dok-4, which is also expressed in T cells, remains unknown. In this study, we report that Dok-4 is phosphorylated after TCR engagement and shuttled within the cytoplasm of T cells before being recruited to the polarized microtubule organizing center after the formation of the immunological synapse. Loss-of-function experiments using RNA interference constructs show that Dok-4 is a negative regulator of ERK phosphorylation, IL-2 promoter activity, and T cell proliferation. Exogenous expression of wild-type Dok-4 induces a significant activation of Rap1, which is involved in the regulation of ERK. The pleckstrin homology domain of Dok-4 is required both for its cytoplasmic shuttling and relocalization as well as for its inhibitory properties on T cell activation. Thus, Dok-4 represents a novel negative regulator of T cells. The Journal of Immunology, 2009, 182: 7681-7689.