...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex
【24h】

FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex

机译:FGF受体4(FGFR4)多态性充当1型膜基质金属蛋白酶-FGFR4复合物的活性开关

获取原文
获取原文并翻译 | 示例
           

摘要

Tumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion and metastasis. However, the signaling mechanisms that underlie MT1-MMP regulation in cancer have remained unclear. Using a systematic gain-of-function kinome screen for MT1-MMP activity, we have here identified kinases that significantly enhance MT1-MMP activity in tumor cells. In particular, we discovered an MT1-MMP/FGF receptor-4 (FGFR4) membrane complex that either stimulates or suppresses MT1-MMP and FGFR4 activities, depending on a tumor progression-associated polymorphism in FGFR4. The FGFR4-R388allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. FGFR4-R388 induced MT1-MMP phosphorylation and endosomal stabilization, and surprisingly, the increased MT1-MMP in return enhanced FGFR4-R388 autophosphorylation. A phosphorylation-defective MT1-MMP was stabilized on the cell surface, where it induced simultaneous FGFR4-R388 internalization and dissociation of cell-cell junctions. In contrast, the alternative FGFR4-G388 variant down-regulated MT1-MMP, and the overexpression of MT1-MMP and particularly its phosphorylation-defective mutant vice versa induced FGFR4-G388 degradation. These results provide a mechanistic basis for FGFR4-R388 function in cancer invasion.
机译:肿瘤细胞使用1型膜基质金属蛋白酶(MT1-MMP)进行侵袭和转移。然而,尚不清楚MT1-MMP调节的癌症信号传导机制。使用针对MT1-MMP活性的系统功能获得的激酶组筛查,我们在这里确定了可显着增强肿瘤细胞MT1-MMP活性的激酶。特别是,我们发现了一个MT1-MMP / FGF受体4(FGFR4)膜复合物,它可以刺激或抑制MT1-MMP和FGFR4的活性,这取决于FGFR4中与肿瘤进展相关的多态性。 FGFR4-R388等位基因与不良的癌症预后相关,通过减少溶酶体MT1-MMP降解而增加了胶原蛋白的侵袭。 FGFR4-R388诱导MT1-MMP磷酸化和内体稳定,令人惊讶的是,增加的MT1-MMP反过来又增强了FGFR4-R388自磷酸化。磷酸化缺陷的MT1-MMP稳定在细胞表面上,在该表面上它诱导FGFR4-R388同时发生内在化和细胞-细胞连接的解离。相反,替代的FGFR4-G388变体下调了MT1-MMP,而MT1-MMP的过表达,尤其是其磷酸化缺陷的突变体,反之亦然,导致FGFR4-G388降解。这些结果为FGFR4-R388在癌症侵袭中的功能提供了机械基础。

著录项

  • 来源
  • 作者单位

    Molecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland Genome-Scale Biology Research Program, Research Programs Unit, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

    rnGenome-Scale Biology Research Program, Research Programs Unit, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

    rnMolecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland Genome-Scale Biology Research Program, Research Programs Unit, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

    rnMolecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

    rnDepartment of Biochemistry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam,Hong Kong;

    rnDepartment of Biochemistry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam,Hong Kong;

    rnMolecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

    rnGenome-Scale Biology Research Program, Research Programs Unit, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland Department of Biosciences and Nutrition, Karolinska Institutet, SE-17177 Stockholm, Sweden;

    rnMolecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

    rnMolecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland Genome-Scale Biology Research Program, Research Programs Unit, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    proteolysis; signaling; MMP14; ECM; invasion;

    机译:蛋白水解发信号MMP14;ECM;侵入;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号