...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants
【24h】

Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants

机译：IA类PI 3-激酶的调节：C2域-iSH2域接触抑制p85 /p110α并在致癌性p85突变体中被破坏

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

We previously proposed a model of Class IA PI3K regulation in which p85 inhibition of p110α requires (i) an inhibitory contact between the p85 nSH2 domain and the p110α helical domain, and (ii) a contact between the p85 nSH2 and iSH2 domains that orients the nSH2 so as to inhibit p110α. We proposed that oncogenic truncations of p85 fail to inhibit p110 due to a loss of the iSH2-nSH2 contact. However, we now find that within the context of a minimal regulatory fragment of p85 (the nSH2-iSH2 fragment, termed p85ni), the nSH2 domain rotates much more freely (τ_c≈ 12.7 ns) than it could if it were interacting rigidly with the iSH2 domain. These data are not compatible with our previous model. We therefore tested an alternative model in which oncogenic p85 truncations destabilize an interface between the p110α C2 domain (residue N345) and the p85 iSH2 domain (residues D560 and N564). p85ni-D560K/N564K shows reduced inhibition of p110α, similar to the truncated p85ni-572~(STOP). Conversely, wild-type p85ni poorly inhibits p110αN345K. Strikingly, the p110αN345K mutant is inhibited to the same extent by the wild-type or truncated p85ni, suggesting that mutation of p110α-N345 is not additive with the p85ni-572~(STOP) mutation. Similarly, the D560K/N564K mutation is not additive with the p85ni-572~(STOP) mutant for downstream signaling or cellular transformation. Thus, our data suggests that mutations at the C2-iSH2 domain contact and truncations of the iSH2 domain, which are found in human tumors, both act by disrupting the C2-iSH2 domain interface.
机译：我们先前提出了IA类PI3K调节模型，其中p85对p110α的抑制需要（i）p85 nSH2结构域与p110α螺旋结构域之间的抑制接触，以及（ii）p85 nSH2与iSH2结构域之间的抑制接触nSH2从而抑制p110α。我们提出，由于iSH2-nSH2接触的丧失，致癌性的p85截短不能抑制p110。但是，我们现在发现，在p85的最小调控片段（nSH2-iSH2片段，称为p85ni）的背景下，nSH2域的旋转自由度（τ_c≈12.7 ns）要比与之刚性相互作用时的旋转自由得多。 iSH2域。这些数据与我们以前的模型不兼容。因此，我们测试了一种替代模型，其中致癌性p85截短使p110αC2域（残基N345）和p85 iSH2域（残基D560和N564）之间的界面不稳定。 p85ni-D560K / N564K对p110α的抑制作用降低，类似于截短的p85ni-572〜（STOP）。相反，野生型p85ni对p110αN345K的抑制作用较弱。令人惊讶的是，p110αN345K突变体被野生型或截短的p85ni抑制的程度相同，这表明p110α-N345突变不会与p85ni-572〜（STOP）突变相加。类似地，D560K / N564K突变与p85ni-572〜（STOP）突变体不相加，可用于下游信号传导或细胞转化。因此，我们的数据表明在人类肿瘤中发现的C2-iSH2结构域接触处的突变和iSH2结构域的截短均通过破坏C2-iSH2结构域界面起作用。

著录项

  • 来源
  • 作者

    Haiyan Wu; S. Chandra Shekar; Rory J. Flinn; Mirvat El-Sibai; Bijay S. Jaiswal; K. Ilker Sen; Vasantharajan Janakiraman; Somasekar Seshagiri; Gary J. Gerfen; Mark E. Girvin; Jonathan M. Backer;

  • 作者单位

    Departments of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

    Departments of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

    Departments of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

    Department of Natural Sciences, Lebanese American University, Beirut Campus, Beirut, Lebanon;

    Department of Molecular Biology, Genetech Inc., 1 DNA Way, South San Francisco, CA 94080;

    Departments of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

    Department of Molecular Biology, Genetech Inc., 1 DNA Way, South San Francisco, CA 94080;

    Department of Molecular Biology, Genetech Inc., 1 DNA Way, South San Francisco, CA 94080;

    Departments of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

    Departments of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

    Departments of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461;

  • 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

    cancer; glioblastoma; phosphoinositide 3-kinase; PIK3CA;

    机译：癌症;胶质母细胞瘤磷酸肌醇3-激酶;PIK3CA;

相似文献

  • 外文文献
  • 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