HERBIMYCIN-A INDUCES THE 20S PROTEASOME-DEPENDENT AND UBIQUITIN-DEPENDENT DEGRADATION OF RECEPTOR TYROSINE KINASES
HERBIMYCIN-A INDUCES THE 20S PROTEASOME-DEPENDENT AND UBIQUITIN-DEPENDENT DEGRADATION OF RECEPTOR TYROSINE KINASES
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DOI：
10.1074/jbc.270.28.16580
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发表时间：
1995-07-14
影响因子：
4.8
通讯作者：
ROSEN, N
中科院分区：
文献类型：
--
作者：
SEPPLORENZINO, L;MA, ZP;ROSEN, N
Herbimycin A是一种分离的安莎霉素抗生素，作为逆转由v-src诱导的形态转化的试剂。尽管除莠霉素A被广泛用作抑制多种酪氨酸蛋白激酶和酪氨酸激酶激活的信号转导的工具，但其作用机制尚未明确，包括酪氨酸激酶蛋白水平和活性的降低（Uehara，Y.，Murakami，Y.，美国，Sugimoto，Y.，和Mizuno，S，（1989）Cancer Res.49，780-785）。我们现在表明，除莠霉素A诱导的跨膜酪氨酸激酶受体，如胰岛素样生长因子，胰岛素和表皮生长因子受体的总细胞活性的深刻下降。20 S蛋白酶体抑制剂可阻止胰岛素样生长因子-胰岛素受体的加速降解，而促溶酶体剂和一般的丝氨酸-和半胱氨酸-蛋白酶抑制剂均不能阻止除草霉素A诱导的受体降解。此外，在E1催化的泛素活化缺陷的温度敏感性突变细胞系中，除莠霉素A在限制性温度下的处理不导致胰岛素受体的降解。这些结果表明，除莠霉素A代表了一类新的药物，其靶向通过20 S蛋白酶体降解酪氨酸激酶。这一过程的泛素依赖性表明，这种酪氨酸激酶的降解可能涉及20 S蛋白酶体作为泛素依赖性26 S蛋白酶的蛋白水解核心。
Herbimycin A is an ansamycin antibiotic isolated as an agent that reverses morphological transformation induced by v-src. Although herbimycin A is widely used as a tool for inhibiting multiple tyrosine protein kinases and tyrosine kinase-activated signal transduction, its mechanism of action is not well defined and includes a decrease in both tyrosine kinase protein levels and activity (Uehara, Y., Murakami, Y., Sugimoto, Y., and Mizuno, S, (1989) Cancer Res. 49, 780-785). We now show that herbimycin A induces a profound decrease in the total cellular activity of transmembrane tyrosine kinase receptors, such as insulin-like growth factor, insulin, and epidermal growth factor receptors. A substantial proportion of the in vivo inhibition could be explained by an increase in the rate of degradation, The enhanced degradation of insulin-like growth factor-insulin receptor was prevented by inhibitors of the 20S proteasome, whereas neither lysosomotropic agents nor general serine- and cysteine-protease inhibitors were active in preventing receptor degradation induced by herbimycin A. Moreover, in a temperature-sensitive mutant cell line defective in the E1-catalyzed activation of ubiquitin, herbimycin A treatment at the restrictive temperature did not result in the degradation of insulin receptor, These results suggest that herbimycin A represents a novel class of drug that targets the degradation of tyrosine kinases by the 20S proteasome. The ubiquitin dependence of this process indicates that this degradation of tyrosine kinases might involve the 20S proteasome as the proteolytic core of the ubiquitin-dependent 26S protease.