MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling
MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling
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DOI：
10.1158/1541-7786.mcr-06-0204
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发表时间：
2006-11-01
影响因子：
5.2
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
--
作者：
Ren, Jian;Raina, Deepak;Kufe, Donald
成纤维细胞生长因子（FGF）受体3（FGFR 3）的激活与人类癌症的发生有关，其机制尚不清楚。MUC 1癌蛋白在某些恶性血液病和大多数人类肿瘤中异常过表达。目前的研究表明MUC 1与FGFR 3相关。用FGF 1刺激细胞增加了MUC 1和FGFR 3之间的相互作用。FGF 1刺激还诱导MUC 1胞质结构域上YEKV基序的c-Src依赖性酪氨酸磷酸化。FGF 1诱导的MUC 1的酪氨酸磷酸化与MUC 1与β-连环蛋白的结合增加以及MUC 1和β-连环蛋白靶向细胞核相关。FGF 1还通过依赖于YEKV基序磷酸化的机制诱导MUC 1与热休克蛋白90（HSP 90）伴侣的结合。值得注意的是，β-连环蛋白和HSP 90竞争结合MUC 1胞质结构域，表明MUC 1与这些蛋白质形成相互排斥的复合物。结果还显示，用格尔德霉素或17-（烯丙基氨基）-17-去甲氧基格尔德霉素抑制HSP 90减弱了FGF 1诱导的MUC 1与HSP 90的结合以及MUC 1靶向线粒体外膜。这些发现表明FGF 1诱导YEKV上MUC 1的磷酸化，从而激活两种不同的途径：（a）MUC 1和β-连环蛋白的核定位和（B）通过HSP 90将MUC 1递送至线粒体。
Activation of the fibroblast growth factor (FGF) receptor 3 (FGFR3) has been linked to the development of human cancers by mechanisms that are not well understood. The MUC1 oncoprotein is aberrantly overexpressed by certain hematologic malignancies and most human carcinomas. The present studies show that MUC1 associates with FGFR3. Stimulation of cells with FGF1 increased the interaction between MUC1 and FGFR3. FGF1 stimulation also induced c-Src-dependent tyrosine phosphorylation of the MUC1 cytoplasmic domain on a YEKV motif. FGF1-induced tyrosine phosphorylation of MUC1 was associated with increased binding of MUC1 to beta-catenin and targeting of MUC1 and beta-catenin to the nucleus. FGF1 also induced binding of MUC1 to the heat shock protein 90 (HSP90) chaperone by a mechanism dependent on phosphorylation of the YEKV motif. Notably, beta-catenin and HSP90 compete for binding to the MUC1 cytoplasmic domain, indicating that MUC1 forms mutually exclusive complexes with these proteins. The results also show that inhibition of HSP90 with geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin attenuates FGF1-induced binding of MUC1 to HSP90 and targeting of MUC1 to the mitochondrial outer membrane. These findings indicate that FGF1 induces phosphorylation of MUC1 on YEKV and thereby activates two distinct pathways: (a) nuclear localization of MUC1 and beta-catenin and (b) delivery of MUC1 to mitochondria by HSP90.