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Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis.
Leukemia ( IF 11.4 ) Pub Date : 2018-Mar-01 , DOI: 10.1038/leu.2017.267
S Gerboth 1 , E Frittoli 1 , A Palamidessi 1 , F C Baltanas 2 , M Salek 1 , J Rappsilber 1 , C Giuliani 1 , F Troglio 1 , Y Rolland 1 , G Pruneri 3 , S Kreutmair 4 , I Pallavicini 3 , M Zobel 1 , M Cinquanta 5 , S Minucci 3, 4 , C Gomez 2 , E Santos 2 , A L Illert 6, 7 , G Scita 1, 8
Affiliation  

Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although the molecular mechanisms of RAS GEF catalysis have been unveiled, how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro and for platelet-derived growth factor (PDGF) activation of RAC- and RAC-dependent actin remodeling and cell migration. SOS1 is also phosphorylated on Y1196 by BCR-ABL in chronic myelogenous leukemic cells. Importantly, in these cells, SOS1 is required for BCR-ABL-mediated activation of RAC, cell proliferation and transformation in vitro and in a xenograft mouse model. Finally, genetic removal of Sos1 in the bone marrow-derived cells (BMDCs) from Sos1fl/fl mice and infected with BCR-ABL causes a significant delay in the onset of leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, SOS1 is required for full transformation and critically contribute to the leukemogenic potential of BCR-ABL.

中文翻译:

SOS1 在酪氨酸 1196 上的磷酸化促进其 RAC GEF 活性并有助于 BCR-ABL 白血病发生。

Son of Sevenless 1 (SOS1) 是一种双鸟嘌呤核苷酸交换因子 (GEF),可激活小 GTP 酶 RAC 和 RAS。尽管 RAS GEF 催化的分子机制已被揭示,但 SOS1 如何获得 RAC GEF 活性以及该活性的生理病理相关性是什么却知之甚少。在这里,我们显示 SOS1 是由 ABL 在 Y1196 上磷酸化的酪氨酸。Y1196 的磷酸化控制 SOS1 分子间相互作用,是促进体外 RAC 上核苷酸交换以及 RAC 和 RAC 依赖性肌动蛋白重塑和细胞迁移的血小板衍生生长因子 (PDGF) 激活所必需的。SOS1 还在慢性骨髓性白血病细胞中被 BCR-ABL 在 Y1196 上磷酸化。重要的是,在这些细胞中,BCR-ABL 介导的 RAC 激活需要 SOS1,体外和异种移植小鼠模型中的细胞增殖和转化。最后,从 Sos1 遗传去除骨髓衍生细胞 (BMDCs) 中的 Sos1fl/fl小鼠和感染 BCR-ABL 的小鼠一旦将 BMDCs 注射到接受致死照射的小鼠体内,就会显着延迟白血病发生的发生。因此,SOS1 是完全转化所必需的,并且对 BCR-ABL 的致白血病潜力至关重要。
更新日期:2017-09-12
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