MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90
MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90
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DOI：
10.1038/sj.onc.1209012
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Kufe, D
中科院分区：
文献类型：
--
作者：
Ren, J;Bharti, A;Kufe, D
MUC1异二聚体跨膜糖蛋白在大多数人类癌症中异常过表达。MUC1 c末端亚基定位于线粒体并阻断应激诱导的内在凋亡途径的激活。MUC1如何传递到线粒体尚不清楚。目前的研究表明，MUC1与HSP70和HSP90形成细胞内复合物。我们发现MUC1细胞质结构域在体外直接与HSP70结合。相比之下，体外MUC1与HSP90的结合是由c- src介导的MUC1细胞质域磷酸化诱导的。c-Src也增加细胞中MUC1与HSP90的结合。与这些结果一致，我们发现heregulin (HRG)， ErbB受体的配体，激活c-Src，进而刺激MUC1与HSP90的结合。我们还发现c-Src或HSP90抑制剂阻断hrg诱导的MUC1靶向线粒体和MUC1整合到线粒体外膜。这些发现表明MUC1通过激活ErbB受体-c- src途径并通过分子伴侣HSP70/HSP90复合物运输的机制传递到线粒体。
The MUC1 heterodimeric transmembrane glycoprotein is aberrantly overexpressed by most human carcinomas. The MUC1 C-terminal subunit localizes to mitochondria and blocks stress-induced activation of the intrinsic apoptotic pathway. How MUC1 is delivered to mitochondria is not known. The present studies demonstrate that MUC1 forms intracellular complexes with HSP70 and HSP90. We show that the MUC1 cytoplasmic domain binds directly to HSP70 in vitro. By contrast, binding of MUC1 to HSP90 in vitro is induced by c-Src-mediated phosphorylation of the MUC1 cytoplasmic domain. c-Src also increases binding of MUC1 to HSP90 in cells. In concert with these results, we show that heregulin (HRG), a ligand for ErbB receptors, activates c-Src and, in turn, stimulates binding of MUC1 to HSP90. We also show that inhibitors of c-Src or HSP90 block HRG-induced targeting of MUC1 to mitochondria and integration of MUC1 into the mitochondrial outer membrane. These findings indicate that MUC1 is delivered to mitochondria by a mechanism involving activation of the ErbB receptor-c-Src pathway and transport by the molecular chaperone HSP70/HSP90 complex.