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Cell:细胞膜上糖分的另一大作用

来源:生物通 2007-04-11 09:16

    最近,SamuelLunenfeld研究所的JamesDennis博士发现了蛋白上糖的一种新作用。这是《Cell》杂志报道的又一项轰动性实验。

    人体的每个细胞都受感受外界

    刺激的信号途径网络的控制,细胞表面蛋白受体如同细胞的翻译,根据外界刺激指导细胞的分裂或运动。细胞表面有许多这样的蛋白受体,蛋白上携带着复杂的糖。SamuelLunenfeld研究所研究人员发现这些糖的变化经常与癌症、糖尿病和自身免疫性疾病(如多发性硬化等)有关。

    研究结果显示,这些受体蛋白的糖组分控制着蛋白与外界信息相互作用的时间,有效改变一个受体被激活的可能性,阐释了细胞适应营养环境的机制。当这种正常的适应变得不平衡时,会导致癌细胞生长和转移。

    Dennis率领的小组想知道的是,改变荷尔蒙受体蛋白和生长因子受体蛋白上的糖会有什么后果。荷尔蒙受体和生长因子受体是同一类型蛋白,是新一代抗癌药物(如Herceptin)的靶标。SamuelLunenfeld研究所研究主任JimWoodgett说:“这些发现会导致新一类药物治疗方法和策略,改善现有的抗受体药物的效力。”

部分英文原文:

Cell, Vol 129, 123-134, 06 April 2007

Article

Complex N-Glycan Number and Degree of Branching Cooperate to Regulate Cell Proliferation and Differentiation

Ken S. Lau,1,2 Emily A. Partridge,1,3 Ani Grigorian,4 Cristina I. Silvescu,6 Vernon N. Reinhold,6 Michael Demetriou,4,5 and James W. Dennis1,3,

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, ON M5G 1X5, Canada
2 Department of Biochemistry, University of Toronto, ON M5S 1A8, Canada
3 Departments of Molecular & Medical Genetics, Laboratory Medicine and Pathology, University of Toronto, ON M5G 1L5, Canada
4 Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697-4025, USA
5 Department of Neurology, University of California, Irvine, CA 92862-4280, USA
6 Chemistry, University of New Hampshire, Durham, NH 03824, USA

Corresponding author
James W. Dennis
dennis@mshri.on.ca

Summary

The number of N-glycans (n) is a distinct feature of each glycoprotein sequence and cooperates with the physical properties of the Golgi N-glycan-branching pathway to regulate surface glycoprotein levels. The Golgi pathway is ultrasensitive to hexosamine flux for the production of tri- and tetra-antennary N-glycans, which bind to galectins and form a molecular lattice that opposes glycoprotein endocytosis. Glycoproteins with few N-glycans (e.g., TβR, CTLA-4, and GLUT4) exhibit enhanced cell-surface expression with switch-like responses to increasing hexosamine concentration, whereas glycoproteins with high numbers of N-glycans (e.g., EGFR, IGFR, FGFR, and PDGFR) exhibit hyperbolic responses. Computational and experimental data reveal that these features allow nutrient flux stimulated by growth-promoting high-n receptors to drive arrest/differentiation programs by increasing surface levels of low-n glycoproteins. We have identified a mechanism for metabolic regulation of cellular transition between growth and arrest in mammals arising from apparent coevolution of N-glycan number and branching.

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