原癌蛋白c-Cbl促进受体酪氨酸激酶EphA2的降解

Proto-oncogene c-Cbl Promotes the Degradation of EphA2 Receptor Tyrosine Kinase

c Cbl最近被证明是泛素 蛋白酶体 (ubiquitin proteasome)通路中的一个新的RINGFinger型泛素连接酶 (ubiquitinligase ,E3) .c Cbl可以介导受体酪氨酸激酶和非受体酪氨酸受体激酶的降解 .利用内源性表达较高EphA2的大肠癌细胞株HCT1 1 6 ,通过转染野生型c Cbl和显性负变异体(dominantnegativemutant)c Cbl 70Z ,探讨c Cbl在EphA2降解中的作用 .结果显示 ,c Cbl可促进磷酸化EphA2的降解 ,EphA2的降解必须依赖其配体ephrin A1的刺激 ;利用蛋白酶体 (proteasome)抑制剂MG1 32可抑制磷酸化的EphA2降解 ,提示EphA2的最终降解部位是在蛋白酶体 .研究的结果提示 ,c

The product of proto oncogene c Cbl has been proved as a new ubiquitin ligase (E3) of RING finger type for ubiquitin proteasome pathway. Some studies reported that c Cbl exerted the negative regulation to receptor tyrosine kinases and non receptor tyrosine kinases by promoting their degradation. Eph receptor is the largest subfamily of receptor tyrosine kinase, but understanding of the activity regulation to this subfamily is quite poor. It has been demonstrated in our previous study that c Cbl could negatively regulate the activity of EphA2 with an unknown mechanism. In this communication, it was shown that c Cbl mediated degradation of EphA2 after it was activated by the ligand binding. It was also shown that EphA2 was rapidly degraded in response to the ligand stimulation, and this degradation could be blocked by MG132, an inhibitor of proteasome activity. Based on this result, it was proposed that c Cbl might serve as E3 to mediate the ubiquitination of EphA2 and promoted its degradation in proteasome.