CD45 is the most prominent membrane protein on lymphocytes. The function and regulation of this protein tyrosine phosphatase remain largely obscure, mainly because of the lack of a known ligand, and it still remains unknown whether such tyrosine phosphatases are subject to extracellular control at all. We report that an anti-CD45RB antibody (Ab) that prevents rejection and induces tolerance activates CD45RB tyrosine phosphatase enzymatic activity in T lymphocytes, allowing us to directly monitor the effects of increased CD45RB activity on signal transduction. Using both kinase substrate peptide arrays as well as conventional biochemistry, we also provide evidence of the various kinases involved in bringing about the inhibitory effect of this Ab on CD3-induced T-cell receptor signaling. Furthermore, we report that activated CD45RB translocates to lipid rafts and interferes with lipid raft localization and activation state of CD45 substrate Lck. Thus, these findings indeed prove that CD45 is subject to extracellular control and also define a novel mechanism by which receptor tyrosine phosphatases control lymphocyte biology and provide further insight into the intracellular signaling pathways effected by anti-CD45RB monoclonal Ab treatment.

译文

CD45是淋巴细胞上最突出的膜蛋白。这种蛋白质酪氨酸磷酸酶的功能和调节在很大程度上仍然不清楚,这主要是由于缺乏已知的配体,并且仍然未知这种酪氨酸磷酸酶是否完全受细胞外控制。我们报告了一种防止排斥和诱导耐受性的anti-CD45RB抗体 (Ab) 激活T淋巴细胞中的CD45RB酪氨酸磷酸酶酶活性,使我们能够直接监测CD45RB活性增加对信号转导的影响。使用激酶底物肽阵列以及常规生物化学,我们还提供了涉及这种Ab对CD3-induced T细胞受体信号传导的抑制作用的各种激酶的证据。此外,我们报道活化的CD45RB易位于脂筏,并干扰CD45底物Lck的脂筏定位和激活状态。因此,这些发现确实证明了CD45受细胞外控制,并且还定义了一种新的机制,通过该机制受体酪氨酸磷酸酶控制淋巴细胞生物学,并提供了对anti-CD45RB单克隆Ab治疗所影响的细胞内信号通路的进一步了解。

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