Ligand-induced Ubiquitination of Receptor Tyrosine Kinases

我们以前曾报道，大多数单体受体酪氨酸激酶经历配体诱导的多泛素化，泛素化受体被26S蛋白降解，并假设配体诱导的受体泛素化及其蛋白酶体降解是受体酪氨酸激酶下调信号转导的新机制。在本研究中，我们试图鉴定一种可能的泛素化机制的酶组分，以阐明受体泛素化的分子机制。我们发现c-Cbl在血小板衍生生长因子受体的泛素化过程中起着重要的作用；c-Cbl与PDGFβ受体的羧基末端结合，这是我们先前确定的酶的泛素化系统的识别部位；c-Cb1与受体的结合是受体泛素化所必需的；v-Cbl显性地与c-Cbl与受体结合，从而干扰受体的泛素化，导致受体信号的加速。我们目前的研究首次揭示了v-Cbl致癌作用的分子机制，并为寻找受体酪氨酸激酶泛素化系统的酶组分提供了第一条线索。

We have previously reported that most of the monomeric receptor tyrosine kinases undergo ligand-induced polyubiquitination and the ubiquitinated receptors are degraded by 26S proteasorne, and postulated that the ligand-induced receptor ubiquitination and subsequent its proteasomal degradation is a novel mechanism for down-regulation of signal transduction by the receptor tyrosine kinases, In the present study, we have tried to identify enzymatic components of a possible ubiquitination machinery, in order to clarify the molecular mechanism of the receptor ubiquitination. We have found that c-Cbl plays an important role in the ubiquitination process of the platelet-derived growth factor receptors ; c-Cbl binds to a carboxyl-terminal stretch of the PDGF beta-receptor, which have been previously identified by us as a recognition site of the ubiquitination system of enzymes ; the binding of c-Cbl to the receptor is necessary for the receptor ubiquitination ; v-Cbl dominant-negatively competes for the binding of c-Cbl to the receptor, thereby interferes with the receptor ubiquitination, resulting in acceleration of the receptor signaling. Our current study reveals for the first time the rn6lecular mechanism of the oncogenic effect of v-Cbl and, furthermore, provides the first crue to search for the enzymatic components of the ubiquitination system for receptor tyrosine kinases.