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首页> 美国卫生研究院文献>Molecular Cellular Proteomics : MCP >Linker for Activation of T-cell Family Member2 (LAT2) a Lipid Raft Adaptor Protein for AKT Signaling Is an Early Mediator of Alkylphospholipid Anti-leukemic Activity
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Linker for Activation of T-cell Family Member2 (LAT2) a Lipid Raft Adaptor Protein for AKT Signaling Is an Early Mediator of Alkylphospholipid Anti-leukemic Activity

机译：T细胞家族成员2（LAT2）的脂筏适配器蛋白的AKT信号的激活的链接器是烷基磷脂抗白血病活性的早期介质。

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Lipid rafts are highly ordered membrane domains rich in cholesterol and sphingolipids that provide a scaffold for signal transduction proteins; altered raft structure has also been implicated in cancer progression. We have shown that 25 μm 10-(octyloxy) decyl-2-(trimethylammonium) ethyl phosphate (ODPC), an alkylphospholipid, targets high cholesterol domains in model membranes and induces apoptosis in leukemia cells but spares normal hematopoietic and epithelial cells under the same conditions. We performed a quantitative (SILAC) proteomic screening of ODPC targets in a lipid-raft-enriched fraction of leukemic cells to identify early events prior to the initiation of apoptosis. Six proteins, three with demonstrated palmitoylation sites, were reduced in abundance. One, the linker for activation of T-cell family member 2 (LAT2), is an adaptor protein associated with lipid rafts in its palmitoylated form and is specifically expressed in B lymphocytes and myeloid cells. Interestingly, LAT2 is not expressed in K562, a cell line more resistant to ODPC-induced apoptosis. There was an early loss of LAT2 in the lipid-raft-enriched fraction of NB4 cells within 3 h following treatment with 25 μm ODPC. Subsequent degradation of LAT2 by proteasomes was observed. Twenty-five μm ODPC inhibited AKT activation via myeloid growth factors, and LAT2 knockdown in NB4 cells by shRNA reproduced this effect. LAT2 knockdown in NB4 cells also decreased cell proliferation and increased cell sensitivity to ODPC (7.5×), perifosine (3×), and arsenic trioxide (8.5×). Taken together, these data indicate that LAT2 is an early mediator of the anti-leukemic activity of alkylphospholipids and arsenic trioxide. Thus, LAT2 may be used as a target for the design of drugs for cancer therapy.
机译：脂质筏是富含胆固醇和鞘脂的高度有序的膜结构域，为信号转导蛋白提供了支架。筏结构的改变也与癌症的进展有关。我们已经显示25μm的10-（辛氧基）癸基-2-（三甲基铵）乙基磷酸酯（ODPC）（一种烷基磷脂）靶向模型膜中的高胆固醇域，并诱导白血病细胞凋亡，但在相同的条件下可以保留正常的造血和上皮细胞条件。我们对富含脂质筏的白血病细胞部分中的ODPC靶标进行了定量（SILAC）蛋白质组学筛选，以鉴定凋亡开始之前的早期事件。六个蛋白质，三个具有已证明的棕榈酰化位点，数量减少。一种是激活T细胞家族成员2（LAT2）的接头，是一种与脂筏相关的衔接蛋白，其棕榈酰化形式存在于B淋巴细胞和髓样细胞中。有趣的是，LAT2在K562（一种对ODPC诱导的细胞凋亡更具抵抗力的细胞系）中不表达。用25μmODPC处理后3小时内，富含脂质筏的NB4细胞中LAT2的早期丢失。后来观察到蛋白酶体降解了LAT2。 25μmODPC通过髓样生长因子抑制AKT活化，shRNA在NB4细胞中的LAT2敲低可重现该效应。 NB4细胞中的LAT2敲低还降低了细胞增殖，并提高了对ODPC（7.5x），periposine（3x）和三氧化二砷（8.5x）的细胞敏感性。总而言之，这些数据表明LAT2是烷基磷脂和三氧化二砷的抗白血病活性的早期介体。因此，LAT2可用作设计用于癌症治疗的药物的靶标。

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