Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL-5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL.
Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL-5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL.
复制标题
Lyn 在 CEL 中介导 FIP1L1-PDGFRA 信号通路通过 FIP1L1-PDGFRA/JAK2/Lyn/Akt 网络复合物促进 IL-5RA 细胞内信号
DOI：
10.18632/oncotarget.11401
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发表时间：
2017-09-12
期刊：
影响因子：
--
通讯作者：
Duan C
中科院分区：
文献类型：
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作者：
Li B;Zhang G;Li C;Li R;Lu J;He Z;Wang Q;Peng Z;Wang J;Dong Y;Zhang C;Tan JQ;Bahri N;Wang Y;Duan C
FIP 1样1（FIP 1 L1）-血小板衍生生长因子受体α（PDGFRA）（F/P）癌基因可引起慢性嗜酸性粒细胞白血病（CEL），但需要IL-5细胞因子参与。本研究旨在探讨F/P与IL-5协同作用在CEL中的作用机制。结果表明，林恩是IL-5激发的嗜酸性粒细胞产生的关键效应子，在F/P阳性CEL细胞中被广泛激活。林恩可使F/P阳性细胞中的IL-5受体α（IL-5 RA）结合并磷酸化。IL-5刺激后，细胞林恩激酶和IL-5 R激酶的活化增强。F/P阳性CEL细胞中的林恩抑制减弱细胞增殖，诱导凋亡，并阻断细胞迁移和主要碱性蛋白（MBP）释放。我们鉴定了F/P表达细胞中的FIP 1 L1-PDGFRA/JAK 2/林恩/Akt复合物，其可被JAK 2和林恩的双重抑制破坏，从而抑制EOL-1（F/P阳性人嗜酸性细胞系）和伊马替尼耐药（IR）细胞中的细胞增殖。总之，我们的数据表明，林恩是一个重要的下游激酶激活的F/P收敛与IL-5信号在CEL细胞。林恩通过FIP 1 L1-PDGFRA/JAK 2/林恩/Akt网络复合物激活和扩大IL-5 RA细胞内信号传导，引起嗜酸性粒细胞增殖和过度激活，表现为CEL。
The Fip1-like1 (FIP1L1)–platelet-derived growth factor receptor alpha (PDGFRA) (F/P) oncogene can cause chronic eosinophilic leukemia (CEL), but requires IL-5 cytokine participation. In this study, we investigate the mechanism of F/P in collaboration with IL-5 in CEL. The results showed that Lyn, a key effector in the IL-5-motivated eosinophil production, is extensively activated in F/P-positive CEL cells. Lyn can associate and phosphorylate IL-5 receptor α (IL-5RA) in F/P-positive cells. Moreover, the activation of Lyn and IL-5R kinase were strengthened when the cells were stimulated by IL-5. Lyn inhibition in F/P-positive CEL cells attenuated cellular proliferation, induced apoptosis, and blocked cell migration and major basic protein (MBP) release. We identified the FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in the F/P-expressing cells which can be disrupted by dual inhibition of JAK2 and Lyn, repressing cell proliferation in both EOL-1(F/P-positive human eosinophilic cell line) and imatinib-resistance (IR) cells. Altogether, our data demonstrate that Lyn is a vital downstream kinase activated by F/P converged with IL-5 signals in CEL cells. Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.