Modeling the signaling endosome hypothesis: why a drive to the nucleus is better than a (random) walk.
Modeling the signaling endosome hypothesis: why a drive to the nucleus is better than a (random) walk.
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DOI：
10.1186/1742-4682-2-43
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发表时间：
2005-10-19
影响因子：
--
通讯作者：
Howe CL
中科院分区：
文献类型：
--
作者：
Howe CL
从质膜到细胞核的信息传递是一种普遍的细胞生物学特性。这种信息通常以翻译后修饰的蛋白质信使的形式编码。教科书上的信号模型通常依赖于分子信号从质膜的起始点到细胞核内效应器功能的位置的扩散。然而，这样的模型没有考虑到细胞环境对扩散施加的几个关键限制，包括通过去磷酸化终止信号的可能性。相反，与逆行运输的膜结合细胞器相关的信号，如内小体，为分子信号的载体传递提供了一种去磷酸化抵抗机制。我们探讨了信号扩散与信号内体逆行运输的相对效率。结合STAT-3分子扩散的大规模蒙特卡罗模拟和去磷酸化动力学的概率模型，我们发现STAT-3扩散的预测理论指标可能高估了这一信号的有效范围。与逆行运输的信号内体固有的核导向运动相比，STAT-3的扩散在距离质膜200纳米以上的空间域的信息传递中变得不那么有效。我们的模型表明，细胞可能利用两种不同的信息传递范例：1)通过在小于200纳米量级的空间域上扩散的快速局部信号传递；2)通过与细胞骨架运输装置相关的信息包进行远程信号传递。我们的模型支持之前的观察结果，即信号内体假说是更普遍的假说的子集，即细胞内远距离信号传递的最有效机制涉及信号分子与沿细胞骨架移动的分子马达的关联。然而，重要的是，包含配体占据的跨膜受体和下游效应分子的膜结合复合体的细胞骨架结合提供了在传输路径上的任何点再生信号的能力。我们得出结论，信号内体提供了与所有细胞结构相关的独特的信息传递特性，我们认为从质膜到细胞核的大部分相关信息将与内吞起源的细胞器有关。
Information transfer from the plasma membrane to the nucleus is a universal cell biological property. Such information is generally encoded in the form of post-translationally modified protein messengers. Textbook signaling models typically depend upon the diffusion of molecular signals from the site of initiation at the plasma membrane to the site of effector function within the nucleus. However, such models fail to consider several critical constraints placed upon diffusion by the cellular milieu, including the likelihood of signal termination by dephosphorylation. In contrast, signaling associated with retrogradely transported membrane-bounded organelles such as endosomes provides a dephosphorylation-resistant mechanism for the vectorial transmission of molecular signals. We explore the relative efficiencies of signal diffusion versus retrograde transport of signaling endosomes. Using large-scale Monte Carlo simulations of diffusing STAT-3 molecules coupled with probabilistic modeling of dephosphorylation kinetics we found that predicted theoretical measures of STAT-3 diffusion likely overestimate the effective range of this signal. Compared to the inherently nucleus-directed movement of retrogradely transported signaling endosomes, diffusion of STAT-3 becomes less efficient at information transfer in spatial domains greater than 200 nanometers from the plasma membrane. Our model suggests that cells might utilize two distinct information transmission paradigms: 1) fast local signaling via diffusion over spatial domains on the order of less than 200 nanometers; 2) long-distance signaling via information packets associated with the cytoskeletal transport apparatus. Our model supports previous observations suggesting that the signaling endosome hypothesis is a subset of a more general hypothesis that the most efficient mechanism for intracellular signaling-at-a-distance involves the association of signaling molecules with molecular motors that move along the cytoskeleton. Importantly, however, cytoskeletal association of membrane-bounded complexes containing ligand-occupied transmembrane receptors and downstream effector molecules provides the ability to regenerate signals at any point along the transmission path. We conclude that signaling endosomes provide unique information transmission properties relevant to all cell architectures, and we propose that the majority of relevant information transmitted from the plasma membrane to the nucleus will be found in association with organelles of endocytic origin.
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DOI：
10.1002/neu.10323
发表时间：
2004-02-05
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Howe, CL;Mobley, WC
通讯作者：
Mobley, WC
影响因子：
4.1
作者：
Kholodenko, BN;Brown, GC;Hoek, JB
通讯作者：
Hoek, JB
影响因子：
16.2
作者：
Howe, CL;Valletta, JS;Mobley, WC
通讯作者：
Mobley, WC
影响因子：
25
作者：
Heerssen, HM;Pazyra, MF;Segal, RA
通讯作者：
Segal, RA
影响因子：
3.5
作者：
Kikushima, K;Yagi, T;Kamiya, R
通讯作者：
Kamiya, R