Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites.
Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites.
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DOI：
10.1083/jcb.200112066
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发表时间：
2002-07-08
期刊：
影响因子：
--
通讯作者：
Lock P
中科院分区：
文献类型：
--
作者：
Gugasyan R;Quilici C;I ST;Grail D;Verhagen AM;Roberts A;Kitamura T;Dunn AR;Lock P
Dok下游相关蛋白(DokR，又称p56dok/Frip/Dok-R)参与髓系细胞和T细胞的细胞因子和免疫受体信号传导。酪氨酸磷酸化诱导DokR与信号转导分子RasGTP酶激活蛋白(RasGAP)和Nck结合。在这里，我们研究了DokR在造血发育过程中的功能，以及在其生物学功能中对RasGAP和NCK结合位点的要求。逆转录病毒介导的DokR在骨髓细胞中的表达对细胞因子巨噬细胞集落刺激因子和干细胞因子的体外集落形成能力有显著的抑制作用，而对白细胞介素3和粒细胞巨噬细胞集落刺激因子的反应仅有微弱的影响。当被引入致死照射的小鼠中时，表达DokR的造血细胞重新填充淋巴组织的能力显著降低。最值得注意的是，DOKR显著减少了胸腺的重新繁殖，部分是通过减少种植在胸腺中的T细胞前体的数量，但同样地，通过抑制CD 4−CD8−向CD 4+CD 8+T细胞的转变。因此，成熟的外周T细胞数量明显减少。相反，观察到对B细胞和髓系发育的影响很小。重要的是，功能的RasGAP和NCK结合位点被发现对DokR的体内外生物学效应是必不可少的。
Downstream of kinase (Dok)–related protein (DokR, also known as p56dok/FRIP/Dok-R) is implicated in cytokine and immunoreceptor signaling in myeloid and T cells. Tyrosine phosphorylation induces DokR to bind the signal relay molecules, RasGTPase-activating protein (RasGAP) and Nck. Here, we have examined the function of DokR during hematopoietic development and the requirement for RasGAP and Nck binding sites in its biological function. Retroviral-mediated expression of DokR in bone marrow cells dramatically inhibited their capacity to form colonies in vitro in response to the cytokines macrophage colony–stimulating factor and stem cell factor, whereas responses to interleukin-3 and granulocyte macrophage colony–stimulating factor were only weakly affected. When introduced into lethally irradiated mice, hematopoietic cells expressing DokR showed a drastically reduced capacity to repopulate lymphoid tissues. Most notably, DokR dramatically reduced repopulation of the thymus, in part by reducing the number of T cell precursors seeding in the thymus, but equally, through inhibiting the transition of CD4−CD8− to CD4+CD8+ T cells. Consequently, the number of mature peripheral T cells was markedly reduced. In contrast, a minimal effect on B cell and myeloid lineage development was observed. Importantly, functional RasGAP and Nck binding sites were found to be essential for the biological effects of DokR in vitro and in vivo.
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影响因子：
9.2
作者：
Jones, N;Dumont, DJ
通讯作者：
Dumont, DJ
影响因子：
9.2
作者：
Lu, WG;Katz, S;Mayer, BJ
通讯作者：
Mayer, BJ
DOI：
10.1073/pnas.91.16.7717
发表时间：
1994-08-02
影响因子：
11.1
作者：
CACHONGONZALEZ, MB;FENNER, S;BEST, S
通讯作者：
BEST, S
影响因子：
64.5
作者：
Carpino, N;Wisniewski, D;Clarkson, B
通讯作者：
Clarkson, B
影响因子：
56.9
作者：
Clements, JL;Yang, B;Koretzky, GA
通讯作者：
Koretzky, GA