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首页> 外文期刊>Molecular and Cellular Biology >A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase
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A Direct Binding Site for Grb2 Contributes to Transformation and Leukemogenesis by the Tel-Abl (ETV6-Abl) Tyrosine Kinase

机译：Grb2的直接结合位点有助于通过Tel-Abl（ETV6-Abl）酪氨酸激酶的转化和白血病发生。

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A direct binding site for the Grb2 adapter protein is required for the induction of fatal chronic myeloid leukemia (CML)-like disease in mice by Bcr-Abl. Here, we demonstrate direct binding of Grb2 to the Tel-Abl (ETV6-Abl) fusion protein, the product of complex (9;12) chromosomal translocations in human leukemia, via tyrosine 314 encoded by TEL exon 5. A Tel-Abl point mutant (Y314F) and a splice variant without TEL exon 5 sequences (Δe5) lacked Grb2 interaction and exhibited decreased binding and phosphorylation of the scaffolding protein Gab2 and impaired activation of phosphatidylinositol 3-kinase, Akt, and extracellular signal-regulated kinase/mitogen-activated protein kinase in hematopoietic cells. Tel-Abl Y314F and Δe5 were unable to transform fibroblasts to anchorage-independent growth and were defective for B-lymphoid transformation in vitro and lymphoid leukemogenesis in vivo. Previously, we demonstrated that full-length Tel-Abl induced two distinct myeloproliferative diseases in mice: CML-like leukemia similar to that induced by Bcr-Abl and a novel syndrome of small-bowel myeloid infiltration endotoxemia and hepatic and renal failure. Lack of the Grb2 binding site had no effect on development of small bowel syndrome but significantly attenuated the induction of CML-like disease by Tel-Abl. These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins.
机译：通过Bcr-Abl诱导小鼠致命的慢性髓样白血病（CML）样疾病需要Grb2衔接蛋白的直接结合位点。在这里，我们证明了Grb2通过 TEL 外显子编码的酪氨酸314与人白血病中复杂（9; 12）染色体易位的产物Tel-Abl（ETV6-Abl）融合蛋白直接结合。 5.一个Tel-Abl点突变体（Y314F）和一个没有 TEL 外显子5序列（Δe5）的剪接变体缺少Grb2相互作用，并且显示出支架蛋白Gab2的结合和磷酸化降低，并且磷脂酰肌醇3的活化受损。激酶，Akt和造血细胞中的细胞外信号调节激酶/促分裂原活化蛋白激酶。 Tel-Abl Y314F和Δe5无法将成纤维细胞转化为不依赖锚定的生长，并且在体外B淋巴转化和体内淋巴白血病发生方面均存在缺陷。以前，我们证明了全长Tel-Abl会在小鼠中诱发两种不同的骨髓增生性疾病：类似于Bcr-Abl所致的CML样白血病，以及一种小肠髓样浸润内毒素血症和肝肾衰竭的新型综合征。缺乏Grb2结合位点对小肠综合征的发展没有影响，但显着减弱了Tel-Abl对CML样疾病的诱导。这些结果表明，Grb2的直接结合是致癌Abl融合蛋白促白血病发生的常见机制。

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