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首页> 外文期刊>Molecular and Cellular Biology >Interactions of Drosophila Cbl with epidermal growth factor receptors and role of Cbl in R7 photoreceptor cell development.
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Interactions of Drosophila Cbl with epidermal growth factor receptors and role of Cbl in R7 photoreceptor cell development.

机译：果蝇Cbl与表皮生长因子受体的相互作用以及Cbl在R7感光细胞发育中的作用。

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The human proto-oncogene product c-Cbl and a similar protein in Caenorhabditis elegans (Sli-1) contain a proline-rich COOH-terminal region that binds Src homology 3 (SH3) domains of proteins such as the adapter Grb2. Cb1-Grb2 complexes can be recruited to tyrosine-phosphorylated epidermal growth factor (EGF) receptors through the SH2 domain of Grb2. Here we identify by molecular cloning a Drosophila cDNA encoding a protein (Drosophila Cbl [D-Cbl]) that shows high sequence similarity to the N-terminal region of human c-Cbl but lacks proline-rich sequences and fails to bind Grb2. Nonetheless, in COS-1 cells, expression of hemagglutinin epitope-tagged D-Cbl results in its coimmunoprecipitation with EGF receptors in response to EGF. EGF also caused tyrosine phosphorylation of D-Cbl in such cells, but no association of phosphatidylinositol 3-kinase was detected in assays using anti-p85 antibody. A point mutation in D-Cbl (G305E) that suppresses the negative regulation of LET-23 by the Cbl homolog Sli-1 in C. elegans prevented tyrosine phosphorylation of D-Cbl as well as binding to the liganded EGF receptor in COS-1 cells. Colocalization of EGF receptors with both endogenous c-Cbl or expressed D-Cbl in endosomes of EGF-treated COS-1 cells is also demonstrated by immunofluorescence microscopy. In lysates of adult transgenic Drosophila melanogaster, GST-DCbl binds to the tyrosine-phosphorylated 150-kDa torso-DER chimeric receptor. Expression of D-Cbl directed by the sevenless enhancer in intact Drosophila compromises severely the development of the R7 photoreceptor neuron. These data suggest that despite the lack of Grb2 binding sites, D-Cbl functions as a negative regulator of receptor tyrosine kinase signaling in the Drosophila eye by a mechanism that involves its association with EGF receptors or other tyrosine kinases.
机译：人类原癌基因产物c-Cbl和秀丽隐杆线虫（Sli-1）中的类似蛋白质包含富含脯氨酸的COOH末端区域，该区域与蛋白质的Src同源3（SH3）域结合，例如衔接子Grb2。 Cb1-Grb2复合物可以通过Grb2的SH2结构域募集到酪氨酸磷酸化的表皮生长因子（EGF）受体。在这里，我们通过分子克隆鉴定了编码蛋白（果蝇Cbl [D-Cbl]）的果蝇cDNA，该蛋白与人c-Cbl的N端区域显示高度序列相似性，但缺乏富含脯氨酸的序列且无法结合Grb2。尽管如此，在COS-1细胞中，血凝素表位标记的D-Cbl的表达导致其与EGF受体对EGF发生共免疫沉淀。 EGF还在这种细胞中引起D-Cbl的酪氨酸磷酸化，但是在使用抗p85抗体的测定中未检测到磷脂酰肌醇3-激酶的缔合。 D-Cbl（G305E）中的点突变可抑制秀丽隐杆线虫中Cbl同源物Sli-1对LET-23的负调控，从而阻止了D-Cbl的酪氨酸磷酸化以及与COS-1中的配体EGF受体结合细胞。免疫荧光显微镜法也证实了EGF受体与内源性c-Cbl或表达的D-Cbl在EGF处理的COS-1细胞内体中的共定位。在成人转基因果蝇果蝇的裂解物中，GST-DCb1与酪氨酸磷酸化的150kDa躯干-DER嵌合受体结合。在完整的果蝇中，由七面膜增强子指导的D-Cbl表达严重损害了R7感光神经元的发育。这些数据表明，尽管缺乏Grb2结合位点，但D-Cbl通过果蝇与EGF受体或其他酪氨酸激酶相关的机制，在果蝇眼中充当受体酪氨酸激酶信号的负调节剂。

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