D-Cbl, the Drosophila homologue of the c-Cbl proto-oncogene, interacts with the Drosophila EGF receptor in vivo, despite lacking C-terminal adaptor binding sites
D-Cbl, the Drosophila homologue of the c-Cbl proto-oncogene, interacts with the Drosophila EGF receptor in vivo, despite lacking C-terminal adaptor binding sites
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DOI：
10.1038/sj.onc.1201223
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发表时间：
1997-06-05
期刊：
影响因子：
8
通讯作者：
Bowtell, DDL
中科院分区：
文献类型：
--
作者：
Hime, GR;Dhungat, MP;Bowtell, DDL
C-Cbl原癌基因编码一种多结构域的磷酸蛋白，已被证明与广泛的信号蛋白相互作用。然而，c-Cbl在这些复合体中的生化功能尚不清楚。最近对线虫Cbl同源物SLI-1的研究表明，Cbl蛋白可能是EGF受体(EGFR)信号的负调节因子。由于EGFR和其他蛋白酪氨酸激酶受体信号通路在昆虫和脊椎动物之间高度保守，我们寻找了果蝇c-Cbl的同源物进行详细的遗传分析。我们在这里报道了果蝇只有一个与c-cbl同源的基因D-cbl。我们发现D-CBL编码一个52 kDa的蛋白，它与c-Cb1和SLI-1在新的磷酸酪氨酸结合(PTB)和环指结构域上具有高度的相似性。然而，令人惊讶的是，D-Cb1相对于c-Cb1和SLI-1是C端截断的，因此不能结合含有SH3结构域的适配器蛋白，包括果蝇Grb2同源物DRK。虽然D-Cbl蛋白缺乏DRK结合部位，但它仍然可以与酪氨酸磷酸化蛋白结合，或者本身以DER依赖的方式被酪氨酸磷酸化，并与体内激活的果蝇EGF受体(DER)相关联。与D-Cbl在胚胎和成虫依赖模式中的作用一致，D-Cbl在早期胚胎和三龄幼虫的整个成虫的成盘中都有高水平的表达。这项研究为未来D-Chl的遗传分析奠定了基础，旨在深入了解Cbl蛋白在信号转导中的作用。
The c-Cbl proto-oncogene encodes a multidomain phosphoprotein that has been demonstrated to interact with a wide range of signalling proteins. The biochemical function of c-Cbl in these complexes is, however, unclear. Recent studies with the C. elegans Cbl homologue, sli-1, have suggested that Cbl proteins may act as negative regulators of EGF receptor (EGFR) signalling. As the EGFR and other protein tyrosine kinase receptor signalling pathways are highly conserved between insects and vertebrates, we sought a Drosophila homologue of c-Cbl for a detailed genetic analysis. We report here that Drosophila melanogaster has a single gene, D-cbl, that is homologous to c-cbl. We find that D-cbl encodes a 52 kDa protein that has a high degree of similarity to c-Cbl and SLI-1 across novel phosphotyrosine-binding (PTB) and RING finger domains. Surprisingly, however, D-Cbl is C-terminally truncated relative to c-Cbl and SLI-1 and consequently is unable to bind SH3-domain containing adaptor proteins, including the Drosophila Grb2 homologue, Drk. Although the D-Cbl protein lacks Drk binding sites it can nevertheless associate with a tyrosine phosphorylated protein, or is itself tyrosine phosphorylated in an DER dependent manner and associates,vith activated Drosophila EGF receptors (DER) in vivo. Consistent with a role for D-Cbl in DER dependent patterning in the embryo and adult, D-Cbl is expressed at a high level in early embryos and throughout the imaginal discs in third instar larvae. This study forms the basis for future genetic analysis of D-Chl, aimed at gaining insights into the role of Cbl proteins in signal transduction.