Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.
Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma.
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DOI：
10.1038/leu.2017.273
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Chiba S
中科院分区：
文献类型：
--
作者：
Fujisawa M;Sakata-Yanagimoto M;Nishizawa S;Komori D;Gershon P;Kiryu M;Tanzima S;Fukumoto K;Enami T;Muratani M;Yoshida K;Ogawa S;Matsue K;Nakamura N;Takeuchi K;Izutsu K;Fujimoto K;Teshima T;Miyoshi H;Gaulard P;Ohshima K;Chiba S
在50-70%的血管免疫母细胞性T细胞淋巴瘤（AITL）中发现了体细胞G17 V RHOA突变。突变体RHOA缺乏GTP结合能力，表明经典RHOA信号传导中的缺陷。在这里，我们发现了G17 V RHOA的新功能：通过高通量筛选，VAV 1被鉴定为G17 V RHOA特异性结合伴侣。我们发现G17 V RHOA与VAV 1的结合通过174 Tyr的磷酸化增强了其衔接子功能，从而加速了T细胞受体（TCR）信号传导。细胞因子和趋化因子相关途径的富集也通过G17 V RHOA的表达而明显。我们进一步确定了VAV 1突变和一个新的易位，VAV 1-STAP 2，在785例RHOA突变阴性样本（8.2%），而没有41例RHOA突变阳性样本表现出VAV 1突变。在VAV 1-STAP 2中也证实了174 Tyr磷酸化的增强。多激酶抑制剂达沙替尼通过G17 V RHOA和VAV 1-STAP 2表达有效阻断了VAV 1的加速磷酸化和相关的TCR信号传导。磷酸化-VAV 1染色在携带G17 V RHOA和VAV 1突变的临床标本中的频率高于没有突变的临床标本。我们的研究结果表明，G17 V RHOA-VAV 1轴可能为AITL提供新的治疗靶点。
Somatic G17V RHOA mutations were found in 50–70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1–STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1–STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1–STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA–VAV1 axis may provide a new therapeutic target in AITL.
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影响因子：
7.3
作者：
Barreira, Maria;Fabbiano, Salvatore;Bustelo, Xose R.
通讯作者：
Bustelo, Xose R.
DOI：
10.1016/j.biocel.2008.11.006
发表时间：
2009-06-01
影响因子：
4
作者：
Katzav, Shulamit
通讯作者：
Katzav, Shulamit
影响因子：
--
作者：
Chen, Xing-Gui;Huang, He;Lin, Tong-Yu
通讯作者：
Lin, Tong-Yu
影响因子：
11.5
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
通讯作者：
Pandiella, Atanasio
影响因子：
32.4
作者：
Esensten JH;Helou YA;Chopra G;Weiss A;Bluestone JA
通讯作者：
Bluestone JA