Negative regulation of EphA2 receptor by Cbl.
Negative regulation of EphA2 receptor by Cbl.
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DOI：
10.1016/s0006-291x(02)00806-9
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发表时间：
2002-08
影响因子：
3.1
通讯作者：
You-jie Wang;S. Ota;H. Kataoka;M. Kanamori;Z. Li;H. Band;Masamitsu Tanaka;H. Sugimura
中科院分区：
文献类型：
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作者：
You-jie Wang;S. Ota;H. Kataoka;M. Kanamori;Z. Li;H. Band;Masamitsu Tanaka;H. Sugimura
c-Cbl原癌基因产物Cbl已经作为受体和非受体酪氨酸激酶的负调节剂出现，其功能依赖于其最近鉴定的泛素连接酶活性。在这里，我们报告说，EphA 2，Eph受体酪氨酸激酶的成员是负调控的Cbl。由Cbl介导的EphA 2的负调节依赖于EphA 2的活性，因为EphA 2的激酶失活突变体不能由Cbl调节。此外，据报道，Cbl的TKB区域中的点突变（G306 E-Cbl）消除了Cbl与RTK和非受体酪氨酸激酶的结合，从而损害了与活性EphA 2的结合。显性负性突变体70 Z-Cbl在RING指结构域的N-边界中具有17个氨基酸的缺失，使Cbl对EphA 2的负性调节功能失效。这些结果表明Cbl的TKB结构域和RING指结构域对于这种负调节是必需的。
The c-Cbl proto-oncogene product Cbl has emerged as a negative regulator of receptor and non-receptor tyrosine kinases, a function dependent on its recently identified ubiquitin ligase activity. Here, we report that EphA2, a member of Eph receptor tyrosine kinases is negatively regulated by Cbl. The negative regulation of EphA2 mediated by Cbl is dependent on the activity of EphA2, as the kinase inactive mutant of EphA2 cannot be regulated by Cbl. Moreover, a point mutation (G306E-Cbl) in TKB region of Cbl that has been reported to abolish Cbl binding to RTKs and non-receptor tyrosine kinases impaired the binding to active EphA2. The dominant negative mutant 70Z-Cbl, which has a 17-amino acids deletion in the N-boundary of the RING finger domain, defuncted negative regulatory function of Cbl to EphA2. These results demonstrate that the TKB domain and RING finger domain of Cbl are essential for this negative regulation.