Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia.
Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia.
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DOI：
10.1038/srep07978
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发表时间：
2015-01-23
影响因子：
4.6
通讯作者：
Minato N
中科院分区：
文献类型：
--
作者：
Doi K;Imai T;Kressler C;Yagita H;Agata Y;Vooijs M;Hamazaki Y;Inoue J;Minato N
Rap G蛋白信号调节早期胸腺祖细胞中的Notch激活，而Rap激活失调（Raphigh）导致Notch依赖性T细胞急性淋巴细胞白血病（T-ALL）的发生。我们证明了Rap信号是建立Notch依赖性T-ALL细胞系的增殖和白血病发生所必需的。在T-ALL细胞系中，显性负性Rap 1A 17或Rap 1GAP（Sipa 1）的表达减弱了Rap信号，导致位点2处的Notch加工减少，这是由于Adam 10的成熟受损。抑制Rap 1异戊烯化与香叶基香叶基转移酶抑制剂废除其膜锚定高尔基体网络，并导致减少前蛋白转化酶活性所需的Adam 10成熟。外源性表达成熟形式的Adam 10克服了Sipa 1诱导的T-ALL细胞增殖抑制。T-ALL细胞系以Notch信号依赖的方式表达Notch配体，这有助于细胞自主的Notch激活。尽管在Raphigh造血祖细胞体内发育成T-ALL的过程中，初始胸腺母细胞几乎不表达Notch配体，但在侵入胸腺外重要器官的T-ALL细胞中明显表达Notch配体。这些结果揭示了Rap信号在Notch依赖性T-ALL的发生和进展中的关键作用。
The Rap G protein signal regulates Notch activation in early thymic progenitor cells, and deregulated Rap activation (Raphigh) results in the development of Notch-dependent T-cell acute lymphoblastic leukemia (T-ALL). We demonstrate that the Rap signal is required for the proliferation and leukemogenesis of established Notch-dependent T-ALL cell lines. Attenuation of the Rap signal by the expression of a dominant-negative Rap1A17 or Rap1GAP, Sipa1, in a T-ALL cell line resulted in the reduced Notch processing at site 2 due to impaired maturation of Adam10. Inhibition of the Rap1 prenylation with a geranylgeranyl transferase inhibitor abrogated its membrane-anchoring to Golgi-network and caused reduced proprotein convertase activity required for Adam10 maturation. Exogenous expression of a mature form of Adam10 overcame the Sipa1-induced inhibition of T-ALL cell proliferation. T-ALL cell lines expressed Notch ligands in a Notch-signal dependent manner, which contributed to the cell-autonomous Notch activation. Although the initial thymic blast cells barely expressed Notch ligands during the T-ALL development from Raphigh hematopoietic progenitors in vivo, the ligands were clearly expressed in the T-ALL cells invading extrathymic vital organs. These results reveal a crucial role of the Rap signal in the Notch-dependent T-ALL development and the progression.
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DOI：
10.1083/jcb.200609014
发表时间：
2007-02-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nichols JT;Miyamoto A;Olsen SL;D'Souza B;Yao C;Weinmaster G
通讯作者：
Weinmaster G
影响因子：
3.5
作者：
Lee, JS;Ishimoto, A;Yanagawa, S
通讯作者：
Yanagawa, S
影响因子：
5.3
作者：
Murata, K;Hattori, M;Minato, N
通讯作者：
Minato, N
影响因子：
50.3
作者：
Ishida, D;Kometani, K;Minato, N
通讯作者：
Minato, N
影响因子：
10.6
作者：
Edwards DR;Handsley MM;Pennington CJ
通讯作者：
Pennington CJ