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G proteins and their regulators in EGF receptor trafficking and mitochondrial functions.

机译：G蛋白及其在EGF受体运输和线粒体功能中的调节剂。

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摘要

Mechanisms involving heterotrimeric G proteins in the regulation of membrane trafficking are not well understood. Here, we reported Galphas overexpression promotes ligand-dependent degradation of EGFR and Galphas knockdown delays receptor degradation through interaction with RGS-PX1 and Hrs on early endosomes. These observations provide mechanistic insights into the function of Galphas, RGS-PX1 and Hrs in endocytic sorting.;To further understand RGS-PX1's role in EGFR trafficking and/or Galphas signaling regulation in vivo, we generated RGS-PX1 knockout mice and found homozygous mice were embryonic lethal around midgestation. RGS-PX1-null embryos had significant overall growth retardation, defects in neural tube closure and blood vessel formation and dramatic changes in the organization of endocytic compartments, etc.. Taken together, our findings demonstrate an essential role for RGS-PX1in mouse development and provide new insights into its functions in the regulation of endocytosis dynamics.;During our phylogenetic analysis of RGS-PX1, I noticed that C. elegans RGS-PX1 contained a 1000 aa uncharacterized N-terminus. I did a BLAST search on this 1000 aa and found its human homologue, called "unnamed protein product" along with homologues from other species. Among them, the Arabidopsis Thaliana homologue was named AtNOA1 ( Arabidopsis Thaliana Nitric Oxide Associated, 1). Accordingly, we named the human homologue, hNOA1.;We characterized hNOA1 as a large mitochondrial G protein, peripherally associated with the mitochondrial inner membrane facing the matrix. Overexpression and knockdown of hNOA1 led to changes in mitochondrial shape implying effects on mitochondrial dynamics. By carrying out IP-MS analysis of endogenous hNOA1, we found that hNOA1 interacts with Complex I of the electron transport chain and DAP3 (Death Associated Protein 3), a positive apoptosis regulator. Knockdown of hNOA1 reduces ∼ 20% mitochondrial O2 consumption in a Complex I-dependent manner and renders cells more resistant to apoptotic stimuli. Thus, hNOA1 may potentially serve to link mitochondrial dynamics, respiration and apoptosis.;It has been our interest to link RGS-PX1 with hNOA1. In this thesis, I provide further evidence that hNOA1 and RGS-PX1 interact with each other and some preliminary results leading to the hypothesis that the cytosolic hNOA1 promotes EGF receptor downregulation by sequestering RGS-PX1 from early endosomes to the cytosol.
机译：涉及膜运输的调节中涉及异三聚体G蛋白的机制还不太清楚。在这里，我们报道了Galphas的过表达促进了EGFR的配体依赖性降解，而Galphas的敲低通过与RGS-PX1和Hrs在早期内体上的相互作用而延迟了受体的降解。这些观察结果提供了对Galphas，RGS-PX1和Hrs在内吞分选中的功能的机械洞察力;为了进一步了解RGS-PX1在体内EGFR转运和/或Galphas信号传导调节中的作用，我们生成了RGS-PX1敲除小鼠并发现纯合子小鼠在妊娠中期死亡。 RGS-PX1无效的胚胎具有显着的总体生长发育迟缓，神经管闭合和血管形成缺陷以及内吞区隔组织的显着变化等。综上，我们的发现证明了RGS-PX1在小鼠发育和发育中起着至关重要的作用。为我们在调控内吞作用动力学中的功能提供新见解。；在我们对RGS-PX1进行系统发育分析时，我注意到秀丽隐杆线虫RGS-PX1包含一个1000 aa未表征的N末端。我对这1000个氨基酸进行了BLAST搜索，发现了它的人类同源物，称为“未命名的蛋白质产品”，以及其他物种的同源物。其中，拟南芥的同系物被命名为AtNOA1（拟南芥一氧化氮相关，1）。因此，我们将人类同源物命名为hNOA1。我们将hNOA1表征为一种大型的线粒体G蛋白，与面对基质的线粒体内膜外围相关。 hNOA1的过表达和敲低导致线粒体形状的改变，暗示着对线粒体动力学的影响。通过对内源性hNOA1进行IP-MS分析，我们发现hNOA1与电子传输链的复合物I和正凋亡调节剂DAP3（死亡相关蛋白3）相互作用。抑制hNOA1以复杂的I依赖性方式减少了约20％的线粒体O2消耗，并使细胞对凋亡刺激更具抵抗力。因此，hNOA1可能潜在地连接线粒体动力学，呼吸和细胞凋亡。; RGS-PX1与hNOA1的连接是我们的兴趣。在这篇论文中，我提供了进一步的证据，证明hNOA1和RGS-PX1彼此相互作用，并得到一些初步的结果，从而得出了这样的假设：胞质hNOA1通过将RGS-PX1从早期的内体螯合到细胞质中来促进EGF受体下调。

著录项

  • 作者

    Tang, Tingdong.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Molecular.;Chemistry Biochemistry.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 199 p.
  • 总页数 199
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;生物化学;
  • 关键词

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