SHP-1/immunoreceptor tyrosine-based inhibition motif-independent inhibitory signalling through murine natural killer cell receptor Ly-49A in a transfected B-cell line.
SHP-1/immunoreceptor tyrosine-based inhibition motif-independent inhibitory signalling through murine natural killer cell receptor Ly-49A in a transfected B-cell line.
复制标题
在转染的 B 细胞系中，SHP-1/免疫受体酪氨酸通过鼠自然杀伤细胞受体 Ly-49A 抑制基序独立的抑制信号传导。
DOI：
10.1046/j.1365-2567.2000.00046.x
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发表时间：
2000
期刊：
影响因子：
6.4
通讯作者：
Harada,M
中科院分区：
文献类型：
--
作者：
Motoda,K;Takata,M;Kiura,K;Nakamura,I;Harada,M
Ly-49A 是小鼠自然杀伤细胞受体 Ly-49 家族的成员，在识别靶细胞表面的配体（主要组织相容性复合体 (MHC) I 类分子）后抑制细胞毒性。尽管 Ly-49A 在其细胞质尾部具有基于免疫受体酪氨酸的抑制基序 (ITIM)，但对其抑制功能的机制知之甚少。我们在此报告，抗体介导的 B 细胞受体 (BCR) 与转染的 Ly-49A 分子的共连接导致 BCR 诱导的白细胞介素-2 (IL-2) 分泌终止，并轻度减少 B 细胞系 A20 中 Erk1/2 和 p38 丝裂原激活蛋白 (MAP) 激酶的激活。令人惊讶的是，BCR 诱导的钙动员并未受到 BCR 与 Ly-49A 交联的影响。此外，根据 BCR 诱导的 IL-2 分泌测量，用苯丙氨酸取代 ITIM 中的单个酪氨酸残基并不会导致抑制功能完全丧失。删除 N 端 37 个氨基酸肽（包括 ITIM）确实消除了抑制活性。免疫共沉淀实验表明，在诱导酪氨酸磷酸化时，Ly-49A 会招募含有酪氨酸磷酸酶 1 (SHP-1) 的酪氨酸磷酸酶 src 同源 2 (SH2)，但不会招募含有肌醇磷酸酶 (SHIP) 的肌醇磷酸酶 src 同源 2 (SH2)，并且 ITIM 中的酪氨酸残基对于这种相互作用至关重要。这些结果表明，转染的 Ly-49A 在 B 细胞信号传导中利用两种不同的抑制机制：ITIM 依赖性和 ITIM 独立性。
Ly‐49A is a member of the Ly‐49 family of mouse natural killer cell receptors that inhibit cytotoxicity upon recognition of their ligands, the major histocompatibility complex (MHC) class I molecules, on the target cell surface. Although Ly‐49A has an immunoreceptor tyrosine‐based inhibition motif (ITIM) in its cytoplasmic tail, relatively little is known about the mechanisms underlying its inhibitory function. We report here that antibody‐mediated co‐ligation of the B‐cell receptor (BCR) with the transfected Ly‐49A molecule results in abrogation of BCR‐induced interleukin‐2 (IL‐2) secretion and mild reduction in activation of Erk1/2 and p38 mitogen‐activated protein (MAP) kinases in the B‐cell line A20. Surprisingly, BCR‐induced calcium mobilization was unaffected by cross‐linking of BCR with Ly‐49A. Furthermore, substitution of the single tyrosine residue in ITIM with phenylalanine, did not result in a complete loss of inhibitory function, as measured by BCR‐induced IL‐2 secretion. Deletion of the N‐terminal 37 amino acid peptide, which includes the ITIM, did abrogate the inhibitory activity. Co‐immunoprecipitation experiments revealed that, upon induction of tyrosine phosphorylation, Ly‐49A recruits tyrosine phosphatase src‐homology 2 (SH2) containing tyrosine phosphatases‐1 (SHP‐1), but not inositol phosphatase src‐homology 2 (SH2) containing inositol phosphatase (SHIP), and that the tyrosine residue in the ITIM is critical for this interaction. These results suggest that transfected Ly‐49A utilizes two different inhibitory mechanisms in B‐cell signalling: ITIM‐dependent and ITIM‐independent.