Ultrasensitization: switch-like regulation of cellular signaling by transcriptional induction.
Ultrasensitization: switch-like regulation of cellular signaling by transcriptional induction.
复制标题
超敏化：通过转录诱导对细胞信号传导的开关调节。
DOI：
10.1371/journal.pcbi.0010054
复制
发表时间：
2005-10
影响因子：
4.3
通讯作者：
Herzel, Hanspeter
中科院分区：
文献类型：
--
作者：
Legewie, Stefan;Bluthgen, Nils;Schafer, Reinhold;Herzel, Hanspeter
细胞信号网络在生理和病理条件下都受到转录和蛋白水解调节。例如，已知通过磷酸化进行共价修饰的蛋白质的表达会在细胞分化或致癌过程中发生改变。然而，目前尚不清楚蛋白质表达的适度改变如何引起信号传递的巨大变化，例如，在单倍不足的情况下观察到的，其中信号蛋白的表达减半会废除细胞功能。通过模拟信号转导的基本基序，磷酸化-去磷酸化循环，我们表明，在磷酸化的蛋白质（或磷酸酶）的浓度的微小变化可以影响信号传输中的一个高度超灵敏的方式。这种“超灵敏”是强烈有利于由底物螯合的催化酶，并可以观察到实验测量的酶的速率常数。此外，我们表明，多个蛋白质的协调转录（即，在蛋白激酶级联反应中的共表达）导致关于信号传递的甚至更显著的全或无行为。最后，我们证明了超敏反应可以解释细胞信号转导调控的特异性和模块性。超敏作用可以导致全或无细胞命运决定和高度特异性的细胞调节。此外，开关样现象，如超灵敏度已知有助于双稳态，振荡，降噪，和细胞异质性。激素和其他外部刺激通过调节基因表达诱导细胞转变，如细胞分裂或分化。已知激素诱导的细胞转换以开关样方式发生：当弱背景刺激被拒绝时，一旦超过阈值激素浓度，细胞转换就完全进行。早期的研究已经描述了几种机制，其中这种开关样行为可以通过信号转导网络在细胞内通信中实现，该信号转导网络将激素信号转化为基因表达的改变。作者展示了如何开关样行为可以进一步增强下游的酶诱导的基因表达。他们表明，即使是基因表达的微小改变（酶诱导的）也会显著影响细胞内信号转导网络的活性，从而改变细胞行为。这种现象被称为“超敏感化”。超敏反应可以解释许多疾病相关信号转导蛋白的明显剂量敏感性：例如，两个等位基因（基因拷贝）之一的突变，导致基因表达减少2倍，已经可以启动疾病进展。尽管这种对突变的敏感性可能是有害的，但细胞仍然表现出超敏感性的事实表明，细胞在某种程度上从超敏感性中受益。作者阐述了超敏作用如何提高细胞间通讯的特异性和效率，并有助于细胞记忆。
Cellular signaling networks are subject to transcriptional and proteolytic regulation under both physiological and pathological conditions. For example, the expression of proteins subject to covalent modification by phosphorylation is known to be altered upon cellular differentiation or during carcinogenesis. However, it is unclear how moderate alterations in protein expression can bring about large changes in signal transmission as, for example, observed in the case of haploinsufficiency, where halving the expression of signaling proteins abrogates cellular function. By modeling a fundamental motif of signal transduction, the phosphorylation–dephosphorylation cycle, we show that minor alterations in the concentration of the protein subject to phosphorylation (or the phosphatase) can affect signal transmission in a highly ultrasensitive fashion. This “ultrasensitization” is strongly favored by substrate sequestration on the catalyzing enzymes, and can be observed with experimentally measured enzymatic rate constants. Furthermore, we show that coordinated transcription of multiple proteins (i.e., synexpression) within a protein kinase cascade results in even more pronounced all-or-none behavior with respect to signal transmission. Finally, we demonstrate that ultrasensitization can account for specificity and modularity in the regulation of cellular signal transduction. Ultrasensitization can result in all-or-none cell-fate decisions and in highly specific cellular regulation. Additionally, switch-like phenomena such as ultrasensitization are known to contribute to bistability, oscillations, noise reduction, and cellular heterogeneity. Hormones and other external stimuli induce cellular transitions such as cell division or differentiation by regulating gene expression. Hormone-induced cellular transitions are known to occur in a switch-like fashion: while weak background stimuli are rejected, cellular transitions proceed fully as soon as a threshold hormone concentration is exceeded. Earlier studies have described several mechanisms whereby such a switch-like behavior can be realized in intracellular communication via signal transduction networks, which convert hormonal signals into alterations in gene expression. The authors demonstrate how switch-like behavior can be further enhanced downstream of hormone-induced gene expression. They show that even minor (hormone-induced) alterations in gene expression can dramatically affect the activity of intracellular signal transduction networks, and thereby modify cellular behavior. This phenomenon has been termed “ultrasensitization.” Ultrasensitization can explain the pronounced dosage sensitivity observed for many disease-associated signal transduction proteins: for example, the mutation of one of two alleles (gene copies), resulting in a 2-fold reduction of gene expression, can already initiate disease progression. Although such sensitivity towards mutations is potentially harmful, the fact that cells nevertheless exhibit ultrasensitization suggests that somehow cells benefit from ultrasensitization. The authors illustrate how ultrasensitization improves the specificity and efficiency of cell-to-cell communication and contributes to cellular memory.