The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor α
The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor α
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DOI：
10.1073/pnas.95.14.7927
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发表时间：
1998-07-07
影响因子：
11.1
通讯作者：
Band, H
中科院分区：
文献类型：
--
作者：
Miyake, S;Lupher, ML;Band, H
Cbl原癌基因产物已成为受体和非受体酪氨酸激酶的负调节因子。我们最近证明，致癌Chl突变体在NIH 3T3细胞中表达时上调内源性酪氨酸激酶信号传导机制，并鉴定出血小板衍生生长因子受体α（PDGFR α）是这些癌基因靶向的酪氨酸激酶之一。这些发现表明正常Cbl蛋白在PDGFR α的负调节中的作用。然而，这种负面调节的机制仍有待确定。在这里，我们表明，野生型Cbl的过表达增强配体诱导的PDGFR α的泛素化。同时，与对照细胞相比，Cbl过表达细胞中的PDGPR α经历更快的配体诱导降解。这些结果确定了Cbl在配体诱导的泛素化和受体酪氨酸激酶降解的调节中的作用，并提出了一种潜在的机制，即Cbl对酪氨酸激酶的进化保守的负调控影响。
The Cbl protooncogene product has emerged as a negative regulator of receptor and nonreceptor tyrosine kinases, We recently demonstrated that oncogenic Chl mutants upregulate the endogenous tyrosine kinase signaling machinery when expressed in the NIH 3T3 cells, and identified the platelet-derived growth factor receptor-alpha (PDGFR alpha) as one of the tyrosine kinases targeted by these oncogenes. These findings suggested a role for the normal Cbl protein in negative regulation of the PDGFR alpha. However, the mechanism of such negative regulation remained to be determined. Here we show that overexpression of the wild-type Cbl enhances the ligand-induced ubiquitination of the PDGFR alpha. Concomitantly, the PDGPR alpha in Cbl-overexpressing cells undergoes a faster ligand-induced degradation compared with that in the control cells. These results identify a role for Cbl in the regulation of ligand-induced ubiquitination and degradation of receptor tyrosine kinases and suggest one potential mechanism for evolutionarily conserved negative regulatory influence of Cbl on tyrosine kinases.