Migratory cells exhibit a variety of morphologically distinct responses to their environments that manifest in their cell shape. Some protrude uniformly to increase substrate contacts, others are broadly contractile, some polarize to facilitate migration, and yet others exhibit mixtures of these responses. Prior studies have identified a discrete collection of shapes that the majority of cells display and demonstrated that activity levels of the cytoskeletal regulators Rac1 and RhoA GTPase regulate those shapes. Here, we use computational modeling to assess whether known GTPase dynamics can give rise to a sufficient diversity of spatial signaling states to explain the observed shapes. Results show that the combination of autoactivation and mutually antagonistic cross talk between GTPases, along with the conservative membrane binding, generates a wide array of distinct homogeneous and polarized regulatory phenotypes that arise for fixed model parameters. From a theoretical perspective, these results demonstrate that simple GTPase dynamics can generate complex multistability in which six distinct stable steady states (three homogeneous and three polarized) coexist for a fixed set of parameters, each of which naturally maps to an observed morphology. From a biological perspective, although we do not explicitly model the cytoskeleton or resulting cell morphologies, these results, along with prior literature linking GTPase activity to cell morphology, support the hypothesis that GTPase signaling dynamics can generate the broad morphological characteristics observed in many migratory cell populations. Further, the observed diversity may be the result of cells populating a complex morphological landscape generated by GTPase regulation rather than being the result of intrinsic cell-cell variation. These results demonstrate that Rho GTPases may have a central role in regulating the broad characteristics of cell shape (e.g., expansive, contractile, polarized, etc.) and that shape heterogeneity may be (at least partly) a reflection of the rich signaling dynamics regulating the cytoskeleton rather than intrinsic cell heterogeneity.

中文翻译：

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简单的 RHO GTP 酶动力学生成与细胞形状相关的复杂监管环境

迁移细胞对它们的环境表现出各种形态上不同的反应，这些反应表现在它们的细胞形状上。一些均匀突出以增加基板接触，另一些是广泛收缩的，一些极化以促进迁移，还有一些表现出这些反应的混合。先前的研究已经确定了大多数细胞显示的离散形状集合，并证明细胞骨架调节因子 Rac1 和 RhoA GTPase 的活性水平调节这些形状。在这里，我们使用计算模型来评估已知的 GTPase 动力学是否可以产生足够多样的空间信号状态来解释观察到的形状。结果表明，GTPases 之间的自激活和相互拮抗的串扰相结合，以及保守的膜结合，产生一系列不同的同质和极化调节表型，这些表型因固定模型参数而出现。从理论的角度来看，这些结果表明简单的 GTPase 动力学可以产生复杂的多稳定性，其中六个不同的稳定状态（三个同质和三个极化）对于一组固定的参数共存，每个参数自然映射到观察到的形态。从生物学的角度来看，虽然我们没有明确地模拟细胞骨架或由此产生的细胞形态，但这些结果以及将 GTPase 活性与细胞形态联系起来的先前文献，支持了 GTPase 信号动力学可以产生在许多迁移细胞中观察到的广泛形态特征的假设人口。更多，观察到的多样性可能是细胞填充由 GTPase 调节产生的复杂形态景观的结果，而不是细胞内在变异的结果。这些结果表明，Rho GTPases 可能在调节细胞形状的广泛特征（例如膨胀、收缩、极化等）方面发挥核心作用，形状异质性可能（至少部分）反映了丰富的信号动力学调节细胞骨架而不是内在的细胞异质性。