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首页> 外文期刊>Cancer letters >Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal stromal tumours
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Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal stromal tumours

机译：通过在胃肠道基质肿瘤中阻断分泌物的分泌物贩运分泌物，抑制了致癌物的致癌套件信号传导

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摘要

Abstract Most gastrointestinal stromal tumours (GISTs) are caused by constitutively active mutations in Kit tyrosine kinase. The drug imatinib, a specific Kit inhibitor, improves the prognosis of metastatic GIST patients, but these patients become resistant to the drug by acquiring secondary mutations in the Kit kinase domain. We recently reported that a Kit mutant causes oncogenic signals only on the Golgi apparatus in GISTs. In this study, we show that in GIST, 2- m ethyl co pro p hilin a mide (M-COPA, also known as “AMF-26”), an inhibitor of biosynthetic protein trafficking from the endoplasmic reticulum (ER) to the Golgi, suppresses Kit autophosphorylation at Y703/Y721/Y730/Y936, resulting in blockade of oncogenic signalling. Results of our M-COPA treatment assay show that Kit Y703/Y730/Y936 in the ER are dephosphorylated by protein tyrosine phosphatases (PTPs), thus the ER-retained Kit is unable to activate downstream molecules. ER-localized Kit Y721 is not phosphorylated, but not due to PTPs. Importantly, M-COPA can inhibit the activation of the Kit kinase domain mutant, resulting in suppression of imatinib-resistant GIST proliferation. Our study demonstrates that Kit autophosphorylation is spatio-temporally regulated and may offer a new strategy for treating imatinib-resistant GISTs. Highlights ? Autophosphorylation of Kit mutant at Y703/Y730/Y721/Y936 occurs mainly on the Golgi in GISTs. ? M-COPA blocks Kit trafficking from the ER to the Golgi, leading to suppression of oncogenic signals. ? Kit Y703/Y730/Y936 in the ER are dephosphorylated by protein tyrosine phosphatases. ? M-COPA inhibits oncogenic signalling by targeting drug-resistant Kit mutant.
机译：摘要大多数胃肠道间质肿瘤（GISTS）是由试剂盒酪氨酸激酶中的组成型活性突变引起的。药物伊马替尼是一种特定的试剂盒抑制剂，提高了转移性剂量患者的预后，但通过在试剂盒激酶结构域中获取二次突变，这些患者对药物抵抗力。我们最近报道了套件突变体仅在GOLGI设备上引起致癌信号。在这项研究中，我们表明，在GIST中，2- M乙醇Co Pro P Hilin A MIDE（M-Copa，也称为“AMF-26”），将生物合成蛋白的抑制剂从内质网（ER）中出现给Golgi，抑制Y703 / Y721 / Y730 / Y936的试剂盒自磷酸化，导致致癌信号传导。我们的M-COPA治疗测定结果表明，ER中的试剂盒Y703 / Y730 / Y936通过蛋白酪氨酸磷酸酶（PTP）去磷酸化，因此ER保留的试剂盒不能激活下游分子。 ER局部套件Y721不磷酸化，但不是由于PTPS。重要的是，M-COPA可以抑制试剂盒激酶结构域突变体的激活，导致抑制伊替尼抗性的GIST增殖。我们的研究表明，试剂盒自动磷酸化是时空监管的，并可为治疗伊马替尼抗性的GIST提供新的策略。强调 ？ Y703 / Y730 / Y721 / Y936在Y703 / Y730 / Y721 / Y721 / Y936的胰酸纯磷酸化主要在GOLGI中发生。还M-COPA阻止套件从ER到Golgi的贩运，导致抑制致癌信号。还ER中的套件Y703 / Y730 / Y936通过蛋白质酪氨酸磷酸酶进行了去磷酸化。还M-COPA通过靶向耐药试剂盒突变体来抑制致癌信号传导。

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  • 来源
    《Cancer letters》 |2018年第2018期|共10页
  • 作者

    Yuuki Obata; Keita Horikawa; Isamu Shiina; Tsuyoshi Takahashi; Takatsugu Murata; Yasutaka Tasaki; Kyohei Suzuki; Keita Yonekura; Hiroyasu Esumi; Toshirou Nishida; Ryo Abe;

  • 作者单位

    Division of Immunobiology Research Institute for Biomedical Sciences Tokyo University of Science;

    Division of Immunobiology Research Institute for Biomedical Sciences Tokyo University of Science;

    Department of Applied Chemistry Faculty of Science Tokyo University of Science;

    Department of Surgery Graduate School of Medicine Osaka University;

    Department of Applied Chemistry Faculty of Science Tokyo University of Science;

    Department of Applied Chemistry Faculty of Science Tokyo University of Science;

    Department of Applied Chemistry Faculty of Science Tokyo University of Science;

    Department of Applied Chemistry Faculty of Science Tokyo University of Science;

    Division of Clinical Research Research Institute for Biomedical Sciences University of Science;

    National Cancer Center Hospital;

    Division of Immunobiology Research Institute for Biomedical Sciences Tokyo University of Science;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

    GIST; Kit tyrosine kinase; Imatinib; Golgi apparatus; M-COPA;

    机译：GIST;试剂盒酪氨酸激酶;伊替尼;高尔基装置;M-COPA;

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