BCR-ABL-INDUCED ONCOGENESIS IS MEDIATED BY DIRECT INTERACTION WITH THE SH2 DOMAIN OF THE GRB-2 ADAPTER PROTEIN
BCR-ABL-INDUCED ONCOGENESIS IS MEDIATED BY DIRECT INTERACTION WITH THE SH2 DOMAIN OF THE GRB-2 ADAPTER PROTEIN
复制标题
DOI：
10.1016/s0092-8674(05)80094-7
复制
发表时间：
1993-10-08
期刊：
影响因子：
64.5
通讯作者：
GISHIZKY, ML
中科院分区：
文献类型：
--
作者：
PENDERGAST, AM;QUILLIAM, LA;GISHIZKY, ML
BCR-ABL是一种嵌合癌蛋白，表现出酪氨酸激酶活性失调，并与费城染色体（Ph 1）阳性人类白血病的发病机制有关。BCR第一外显子的序列是激活BCR-ABL转化潜能所必需的，含有SH 2/SH 3结构域的GRB-2蛋白将酪氨酸激酶与Ras信号传导联系起来。我们证明，BCR-ABL存在于一个复杂的GRB-2在体内。GRB-2与BCR-ABL的结合是由GRB-2 SH 2结构域与BCR第一外显子内磷酸化酪氨酸Y177的直接相互作用介导的。BCR-ABL-GRB-2相互作用是激活Ras信号通路所必需的。Y177突变为苯丙氨酸（Y177 F）可消除GRB-2结合并消除BCR-ABL诱导的Ras激活。BCR-ABL（Y177 F）突变体不能转化原代骨髓培养物，其转化Rat 1成纤维细胞的能力受损。这些发现暗示Ras功能的激活是BCR-ABL介导的转化的重要组成部分，并表明GRB-2不仅在正常发育和有丝分裂中起作用，而且在肿瘤发生中起作用。
BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive human leukemias. Sequences within the first exon of BCR are required to activate the transforming potential of BCR-ABL. The SH2/SH3 domain-containing GRB-2 protein links tyrosine kinases to Ras signaling. We demonstrate that BCR-ABL exists in a complex with GRB-2 in vivo. Binding of GRB-2 to BCR-ABL is mediated by the direct interaction of the GRB-2 SH2 domain with a phosphorylated tyrosine, Y177, within the BCR first exon. The BCR-ABL-GRB-2 interaction is required for activation of the Ras signaling pathway. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. The BCR-ABL (Y177F) mutant is unable to transform primary bone marrow cultures and is impaired in its ability to transform Rat1 fibroblasts. These findings implicate activation of Ras function as an important component in BCR-ABL-mediated transformation and demonstrate that GRB-2 not only functions in normal development and mitogenesis but also plays a role in oncogenesis.