Chaoyu Fu, Florian Dilasser, Shao-Zhen Lin, Marc Karnat, Aditya Arora, Harini Rajendiran, Hui Ting Ong, Nai Mui Hoon Brenda, Sound Wai Phow, Tsuyoshi Hirashima, Michael Sheetz, Jean-François Rupprecht, Sham Tlili, Virgile Viasnoff
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引用次数: 0
摘要
细胞集体迁移在伤口愈合、形态发生和癌症转移等各种生理过程中至关重要。粘连接头(AJ)在组织重塑过程中调节细胞内聚力和迁移动力学方面发挥着关键作用。虽然对 AJ 连接处机械张力的作用和起源进行了广泛研究,但对肌动蛋白皮层结构和动态对连接处可塑性的影响仍不甚了解。此外,交界处的应力消散机制也没有得到很好的阐明。在这里,我们发现上皮生长因子受体(EGFR)在新生 E-cadherin 粘附下游的配体非依赖性磷酸化协调了一个反馈回路,通过调节肌动蛋白动力学的 Rac 通路控制细胞间粘度。我们的研究结果突显了依赖于 E-粘连蛋白的表皮生长因子受体活性如何控制细胞集体运动的迁移模式,而不受细胞间张力的影响。这种对有效粘度的调节协调了细胞在扩张单层中的运动,诱导了从漩涡到层流模式的转变,同时保持了恒定的迁移前沿速度。此外,我们还提出了一种具有可调交界粘度的顶点模型,能够复制实验观察到的所有细胞流动表型。
Regulation of intercellular viscosity by E-cadherin-dependent phosphorylation of EGFR in collective cell migration.
Collective cell migration is crucial in various physiological processes, including wound healing, morphogenesis, and cancer metastasis. Adherens Junctions (AJs) play a pivotal role in regulating cell cohesion and migration dynamics during tissue remodeling. While the role and origin of the junctional mechanical tension at AJs have been extensively studied, the influence of the actin cortex structure and dynamics on junction plasticity remains incompletely understood. Moreover, the mechanisms underlying stress dissipation at junctions are not well elucidated. Here, we found that the ligand-independent phosphorylation of epithelial growth factor receptor (EGFR) downstream of de novo E-cadherin adhesion orchestrates a feedback loop, governing intercellular viscosity via the Rac pathway regulating actin dynamics. Our findings highlight how the E-cadherin-dependent EGFR activity controls the migration mode of collective cell movements independently of intercellular tension. This modulation of effective viscosity coordinates cellular movements within the expanding monolayer, inducing a transition from swirling to laminar flow patterns while maintaining a constant migration front speed. Additionally, we propose a vertex model with adjustable junctional viscosity, capable of replicating all observed cellular flow phenotypes experimentally.
期刊介绍:
The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.