Phosphoproteomic analysis reveals interconnected system-wide responses to perturbations of kinases and phosphatases in yeast.
Phosphoproteomic analysis reveals interconnected system-wide responses to perturbations of kinases and phosphatases in yeast.
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DOI：
10.1126/scisignal.2001182
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发表时间：
2010-12-21
影响因子：
7.3
通讯作者：
Aebersold R
中科院分区：
文献类型：
--
作者：
Bodenmiller B;Wanka S;Kraft C;Urban J;Campbell D;Pedrioli PG;Gerrits B;Picotti P;Lam H;Vitek O;Brusniak MY;Roschitzki B;Zhang C;Shokat KM;Schlapbach R;Colman-Lerner A;Nolan GP;Nesvizhskii AI;Peter M;Loewith R;von Mering C;Aebersold R
激酶和磷酸酶对蛋白质的磷酸化和去磷酸化作用构成了真核细胞中一个重要的调控网络。该网络支持从传感器通过信号系统到效应分子的信息流，并最终驱动细胞，组织和生物体的表型和功能。这一过程的失调具有严重后果，并且是包括癌症在内的疾病出现和进展的主要因素之一。因此，主要的努力已经投入到开发特定的抑制剂，调节个别激酶或磷酸酶的活性，但是，它一直难以评估这样的药理学干预将如何影响细胞信号网络作为一个整体。在这里，我们使用无标记，定量磷酸蛋白质组学在系统扰动模式生物（酿酒酵母），以确定97激酶，27磷酸酶，和1000多个磷蛋白之间的关系。我们确定了8814个受调节的磷酸化事件，描述了体内第一个全系统蛋白质磷酸化网络。我们的研究结果表明，在稳定状态下，大多数激酶和磷酸酶的失活影响大部分的磷酸化调节的信号转导机制，而不仅仅是直接的下游目标。尽管存在扰动，但观察到的细胞生长表型通常保持良好，证明系统具有相当的稳健性。我们的研究结果有助于限制未来的细胞信号传导模型，并加强了这样一种想法，即信号传导途径的简单线性表示可能不足以用于药物开发和描述生物体内稳态。
The phosphorylation and dephosphorylation of proteins by kinases and phosphatases constitute an essential regulatory network in eukaryotic cells. This network supports the flow of information from sensors through signaling systems to effector molecules, and ultimately drives the phenotype and function of cells, tissues, and organisms. Dysregulation of this process has severe consequences and is one of the main factors in the emergence and progression of diseases, including cancer. Thus, major efforts have been invested in developing specific inhibitors that modulate the activity of individual kinases or phosphatases; however, it has been difficult to assess how such pharmacological interventions would affect the cellular signaling network as a whole. Here, we used label-free, quantitative phosphoproteomics in a systematically perturbed model organism (Saccharomyces cerevisiae) to determine the relationships between 97 kinases, 27 phosphatases, and more than 1000 phosphoproteins. We identified 8814 regulated phosphorylation events, describing the first system-wide protein phosphorylation network in vivo. Our results show that, at steady state, inactivation of most kinases and phosphatases affected large parts of the phosphorylation-modulated signal transduction machinery, and not only the immediate downstream targets. The observed cellular growth phenotype was often well maintained despite the perturbations, arguing for considerable robustness in the system. Our results serve to constrain future models of cellular signaling and reinforce the idea that simple linear representations of signaling pathways might be insufficient for drug development and for describing organismal homeostasis.
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影响因子：
9.9
作者：
Lange, Vinzenz;Picotti, Paola;Domon, Bruno;Aebersold, Ruedi
通讯作者：
Aebersold, Ruedi
影响因子：
56.9
作者：
Hillenmeyer, Maureen E.;Fung, Eula;Giaever, Guri
通讯作者：
Giaever, Guri
影响因子：
7
作者：
Larsen, MR;Thingholm, TE;Jorgensen, TJD
通讯作者：
Jorgensen, TJD
DOI：
10.1098/rstb.2000.0762
发表时间：
2001-02-28
期刊：
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
Lindquist, S;Krobitsch, S;Sondheimer, N
通讯作者：
Sondheimer, N
影响因子：
3
作者：
Brusniak, Mi-Youn;Bodenmiller, Bernd;Watts, Julian D.
通讯作者：
Watts, Julian D.