Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction.
Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction.
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DOI：
10.1371/journal.pcbi.1006075
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发表时间：
2018-04
影响因子：
4.3
通讯作者：
Klipp E
中科院分区：
文献类型：
--
作者：
Giese W;Milicic G;Schröder A;Klipp E
信号通路的空间结构以及与细胞大小和形态的相互作用很复杂，但人们知之甚少。随着单细胞成像和单细胞生物学的发展，了解细胞内的时间和空间过程变得至关重要。细胞表面受体的活化通常触发信号级联，包括膜附着和胞质信号传导组分的活化，其最终将信号传递到细胞核。信号蛋白可以在胞质溶胶中形成陡峭的梯度，这导致强烈的细胞大小依赖性。我们发现，在膜-胞质界面的动力学和细胞膜面积封闭的胞质体积的比例改变信号级联的行为显着。我们建议根据细胞体积和细胞表面积的任意细胞形状的平均浓度的估计。归一化方差，已知从图像分析，建议作为一种替代措施，以量化偏离平均浓度。对信号在时间和空间上的传递进行了数学分析，给出了线性信号级联在不同空间排列下的解析解。信号传导时间尺度的量化揭示了信号在膜处的传播比在核处的传播更快，而这种时间差随着胞质溶胶中的信号传导组分的数量而减小。我们的调查是补充与反馈和不对称的细胞形状的非线性级联的数值模拟。我们的结论是，细胞内的信号传播是高度依赖于细胞的几何形状，从而，细胞大小和形状的信息传递到细胞核。通常，细胞在其表面检测信号，这些信号被传输到细胞核。细胞的形状和大小的影响往往被忽略，细胞被视为充分混合的隔间。然而，现代显微镜的进步已经揭示了信号分子在细胞中的不均匀分布以及取决于细胞形状，大小和细胞器排列的变化。理解空间信号通常涉及解决空间和时间中的数学方程，包括近似或复杂的数值方法。我们提供了一个通用的线性信号级联模型的两个不同的空间安排的稳态精确的解析解。此外，使用先进的计算技术的动态过程进行了研究。的影响是绘制单细胞的信号转导和空间调节细胞的大小和形状的变化。
The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often triggers a signaling cascade including the activation of membrane-attached and cytosolic signaling components, which eventually transmit the signal to the cell nucleus. Signaling proteins can form steep gradients in the cytosol, which cause strong cell size dependence. We show that the kinetics at the membrane-cytosolic interface and the ratio of cell membrane area to the enclosed cytosolic volume change the behavior of signaling cascades significantly. We suggest an estimate of average concentration for arbitrary cell shapes depending on the cell volume and cell surface area. The normalized variance, known from image analysis, is suggested as an alternative measure to quantify the deviation from the average concentration. A mathematical analysis of signal transduction in time and space is presented, providing analytical solutions for different spatial arrangements of linear signaling cascades. Quantification of signaling time scales reveals that signal propagation is faster at the membrane than at the nucleus, while this time difference decreases with the number of signaling components in the cytosol. Our investigations are complemented by numerical simulations of non-linear cascades with feedback and asymmetric cell shapes. We conclude that intracellular signal propagation is highly dependent on cell geometry and, thereby, conveys information on cell size and shape to the nucleus. Frequently, cells detect signals at their surface, which are transmitted to the nucleus. The influence of cell shape and size is often neglected and cells are regarded as well-mixed compartments. However, the advance of modern microscopy has unraveled heterogeneous distribution of signaling molecules in the cell and variations depending on cell shape, size and organelle arrangement. Understanding spatial signaling usually involves solving mathematical equations in space and time including approximations or sophisticated numerical methods. We provide exact analytical solutions for the steady state of two different spatial arrangements of a generic linear signaling cascade model. Furthermore, the dynamic process is investigated using advanced computational techniques. Implications are drawn on single-cell variation in signal transduction and on spatial regulation by cell size and shape.
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影响因子：
56.9
作者：
Elf, Johan;Li, Gene-Wei;Xie, X. Sunney
通讯作者：
Xie, X. Sunney
影响因子：
10.5
作者：
Dudin O;Merlini L;Martin SG
通讯作者：
Martin SG
DOI：
10.1098/rsif.2016.0409
发表时间：
2016-08
期刊：
Journal of the Royal Society, Interface
影响因子：
--
作者：
Beguerisse-Díaz M;Desikan R;Barahona M
通讯作者：
Barahona M
影响因子：
4.3
作者：
Chay A;Zamparo I;Koschinski A;Zaccolo M;Blackwell KT
通讯作者：
Blackwell KT
影响因子：
3.4
作者：
Berezhkovskii, Alexander M.;Sample, Christine;Shvartsman, Stanislav Y.
通讯作者：
Shvartsman, Stanislav Y.