BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion
BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion
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DOI：
10.1038/sj.onc.1209459
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发表时间：
2006-07-20
期刊：
影响因子：
8
通讯作者：
Miura, O.
中科院分区：
文献类型：
--
作者：
Jin, A.;Kurosu, T.;Miura, O.
Ras家族的小GTPase Rap1被白介素3等造血细胞因子激活，诱导β1整合素介导的细胞黏附，或被BCR/ABL融合酪氨酸激酶激活以刺激MEK/Erk信号通路。在这里，我们证明了SPA-1，一个RAP1特异性的GAP，取消了RAP1的激活，抑制了在IL-3刺激或诱导表达BCR/ABL的小鼠造血细胞系Ton.B210中B-Raf，MEK，Erk和Akt的激活。此外，RAP1失活对Ton.B210细胞的增殖和存活均有抑制作用，在BCR/ABL刺激下抑制作用比IL-3作用更明显。诱导bcr/abl的表达增加了Ton.B210细胞对纤维连接蛋白的黏附，这种黏附至少部分依赖于其激酶活性，而SPA-1对Rap1的抑制部分抑制了bcr/abl诱导的细胞黏附。因此，IL-3或BCR/ABL诱导的Rap1活化可能通过激活B-Raf/MEK/Erk和Akt信号通路，在调节细胞增殖和存活以及诱导整合素介导的细胞黏附中发挥重要作用。此外，与IL-3相比，bcr/abl更依赖于Rap1介导的信号来诱导细胞增殖和存活，因此，Rap1可能成为治疗bcr/abl引起的白血病的新靶点。
The Ras family small GTPase Rap1 is activated by hematopoietic cytokines, such as interleukin (IL)-3, to induce beta 1 integrin-mediated cell adhesion or by the BCR/ABL fusion tyrosine kinase to stimulate the MEK/Erk signaling pathway. Here, we demonstrate that the abrogation of Rap1 activation by SPA-1, a Rap1-specific GAP, inhibits activation of B-Raf, MEK, Erk, and Akt in a murine hematopoietic cell line, Ton.B210, stimulated with IL-3 or inducibly expressing BCR/ABL. Furthermore, Rap1 inactivation had an inhibitory effects on proliferation and survival of Ton.B210 cells, which were more remarkable when cells were stimulated by BCR/ABL than by IL-3. Induction of BCR/ABL expression increased adhesion of Ton.B210 cells to fibronectin in a manner at least partly dependent on its kinase activity, and Rap1 inhibition by SPA-1 partially inhibited BCR/ABL-induced adhesion of cells. Thus, IL-3- or BCR/ABL-induced activation of Rap1 may play important roles in regulation of cell proliferation and survival through activation of the B-Raf/MEK/Erk and Akt signaling pathways and in induction of integrin-mediated cell adhesion. Furthermore, as compared with IL-3, BCR/ABL is more dependent on Rap1-mediated signaling to induce cell proliferation and survival and, thus, Rap1 may represent an attractive target for novel therapies for leukemias caused by BCR/ABL.