Critical role for Gab2 in transformation by BCR/ABL
Critical role for Gab2 in transformation by BCR/ABL
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DOI：
10.1016/s1535-6108(02)00074-0
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发表时间：
2002-06-01
期刊：
影响因子：
50.3
通讯作者：
Neel, BG
中科院分区：
文献类型：
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作者：
Sattler, M;Mohi, MG;Neel, BG
Bcr/abl癌基因在人类引起慢性粒细胞白血病(CML)，在小鼠引起CML样病和淋巴细胞性白血病。P210bcr/abl是一种活化的酪氨酸激酶，可使自身和几种细胞信号蛋白磷酸化。酪氨酸177自动磷酸化位点结合接头Grb2，有助于确定bcr/abl病的谱系和严重程度：Tyr177突变(bcr/abl-Y177F)显著损害髓系白血病的发生，同时减少淋巴白血病的发生。来自Tyr177的关键信号(S)仍然不清楚。我们报道Tyr177通过Grb2/Gab2复合体招募支架适配器Gab2。与表达bcr/abl的BA/F3细胞相比，bcr/abl-Y177F细胞的Gab2酪氨酸磷酸化水平显著降低，磷脂酰肌醇-3激酶(PI3K)和Shp2与Gab2和bcr/ABL的结合显著降低，PI3K/Akt和Ras/Erk的活化、细胞增殖和自发迁移能力降低。值得注意的是，来自Gab2(-/-)小鼠的骨髓祖细胞对bcr/abl的转化具有抵抗力，而淋巴转化则因为显著增加的细胞凋亡而减少。Bcr/abl诱导的PI3K/Akt和RAS/Erk活化在Gab2(-/-)原代髓系和淋巴系细胞中也受到损害。我们的结果确定Gab2及其相关蛋白是决定BCR/ABL转化的谱系和严重程度的关键决定因素。
The BCR/ABL oncogene causes chronic myelogenous leukemia (CML) in humans and a CML-like disease, as well as lymphoid leukemia, in mice. p210 BCR/ABL is an activated tyrosine kinase that phosphorylates itself and several cellular signaling proteins. The autophosphorylation site tyrosine 177 binds the adaptor Grb2 and helps determine the lineage and severity of BCR/ABL disease: Tyr177 mutation (BCR/ABL-Y177F) dramatically impairs myeloid leukemogenesis, while diminishing lymphoid leukemogenesis. The critical signal(s) from Tyr177 has remained unclear. We report that Tyr177 recruits the scaffolding adaptor Gab2 via a Grb2/Gab2 complex. Compared to BCR/ABL-expressing Ba/F3 cells, BCR/ABL-Y177F cells exhibit markedly reduced Gab2 tyrosine phosphoryllation and association of phosphatidylinositol-3 kinase (PI3K) and Shp2 with Gab2 and BCR/ABL, and decreased PI3K/Akt and Ras/Erk activation, cell proliferation, and spontaneous migration. Remarkably, bone marrow myeloid progenitors from Gab2 (-/-) mice are resistant to transformation by BCR/ABL, whereas lymphoid transformation is diminished as a consequence of markedly increased apoptosis. BCR/ABL-evoked PI3K/Akt and Ras/Erk activation also are impaired in Gab2 (-/-) primary myeloid and lymphoid cells. Our results identify Gab2 and its associated proteins as key determinants of the lineage and severity of BCR/ABL transformation.