A new pathway of CD5 glycoprotein-mediated T cell inhibition dependent on inhibitory phosphorylation of Fyn kinase.
A new pathway of CD5 glycoprotein-mediated T cell inhibition dependent on inhibitory phosphorylation of Fyn kinase.
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DOI：
10.1074/jbc.m111.230102
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发表时间：
2011-09-02
期刊：
影响因子：
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通讯作者：
Carmo AM
中科院分区：
文献类型：
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作者：
Bamberger M;Santos AM;Gonçalves CM;Oliveira MI;James JR;Moreira A;Lozano F;Davis SJ;Carmo AM
触发T细胞受体启动信号级联导致T细胞的激活。这些信号与其他受体触发的信号结合在一起，这些受体的功能是调节整体反应。CD5是一种基于免疫酪氨酸的抑制基序受体，通过募集抑制细胞内介质（如SHP-1、RasGAP或Cbl）来拮抗显性T细胞受体激活反应。我们现在提出CD5的抑制作用也通过一个平行途径介导，该途径在Fyn的抑制水平上起作用，Fyn是一种通常与T细胞受体介导的激活相关的激酶。CD5连接后，Fyn的负调节酪氨酸（Tyr531）的磷酸化增加，这与Fyn激酶活性的大幅降低和对ZAP-70激活的深度抑制相关。这种作用需要受体胞质区域的最后23个氨基酸，这强烈暗示了一种新的cd5相互作用信号或衔接蛋白的参与。此外，我们发现在CD5连接后，它的分布发生了深刻的变化，从大流体相到脂质筏环境，在那里它与Fyn、Lck和PAG相关。我们认为，CD5的重新定位（我们也发现它能够形成同型二聚体）使CD5能够通过控制Fyn的磷酸化和活性来抑制膜近端信号传导，可能是通过干扰T细胞活化过程中c端Src激酶(Csk)-PAG-Fyn复合物的分解。
Triggering of the T cell receptor initiates a signaling cascade resulting in the activation of the T cell. These signals are integrated alongside those resulting from the triggering of other receptors whose function is to modulate the overall response. CD5 is an immunotyrosine-based inhibition motif-bearing receptor that antagonizes the overt T cell receptor activation response by recruiting inhibitory intracellular mediators such as SHP-1, RasGAP, or Cbl. We now propose that the inhibitory effects of CD5 are also mediated by a parallel pathway that functions at the level of inhibition of Fyn, a kinase generally associated with T cell receptor-mediated activation. After CD5 ligation, phosphorylation of the negative regulatory tyrosine (Tyr531) of Fyn increases, and this correlates with a substantial reduction in the kinase activity of Fyn and a profound inhibition of ZAP-70 activation. The effect requires the last 23 amino acids of the cytoplasmic domain of the receptor, strongly implying the involvement of a new CD5-interacting signaling or adaptor protein. Furthermore, we show that upon CD5 ligation there is a profound shift in its distribution from the bulk fluid phase to the lipid raft environment, where it associates with Fyn, Lck, and PAG. We suggest that the relocation of CD5, which we also show is capable of forming homodimers, to the proximity of raft-resident molecules enables CD5 to inhibit membrane proximal signaling by controlling the phosphorylation and activity of Fyn, possibly by interfering with the disassembly of C-terminal Src kinase (Csk)-PAG-Fyn complexes during T cell activation.