Cell migration signaling through the EGFR-VAV2-Rac1 pathway is sustained in endosomes.

IF 3.3 3区 生物学 Q3 CELL BIOLOGY Journal of cell science Pub Date : 2025-01-15 Epub Date: 2025-01-24 DOI:10.1242/jcs.263541
Itziar Pinilla-Macua, Sachin Surve, Alexander Sorkin
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Abstract

Ligand binding to EGFR activates Rho family GTPases, triggering actin cytoskeleton reorganization, cell migration and invasion. Activated EGFR is also rapidly endocytosed but the role of EGFR endocytosis in cell motility is poorly understood. Hence, we used live-cell microscopy imaging to demonstrate that endogenous fluorescently labeled VAV2, a guanine nucleotide exchange factor for Rho GTPases, is co-endocytosed with EGFR in genome-edited human oral squamous cell carcinoma (HSC3) cells, an in vitro model for head-and-neck cancer where VAV2 is known to promote metastasis and is associated with poor prognosis. Chemotactic migration of HSC3 cells toward an EGF gradient is found to require both VAV2 and clathrin-mediated endocytosis. Moreover, sustained activation of Rac1, a Rho family GTPase promoting cell migration and a major substrate of VAV2, also depends on clathrin. Endogenous fluorescently labeled Rac1 localizes to EGFR-containing endosomes. Altogether, our findings suggest that signaling through the EGFR-VAV2-Rac1 pathway persists in endosomes and that this endosomal signaling is required for EGFR-driven cell migration.

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通过EGFR-VAV2-Rac1途径的细胞迁移信号在内体中持续存在。
与EGFR结合的配体激活Rho家族gtpase,触发肌动蛋白细胞骨架重组、细胞迁移和侵袭。活化的EGFR也会迅速内吞,但EGFR内吞作用在细胞运动中的作用尚不清楚。因此,我们使用活细胞显微镜成像来证明内源性荧光标记的VAV2 (Rho GTPases的鸟嘌呤核苷酸交换因子)在基因组编辑的人口腔鳞状细胞癌(HSC3)细胞中与EGFR共内吞,HSC3是头颈癌的体外模型,已知VAV2促进转移并与不良预后相关。HSC3细胞向EGF梯度的趋化迁移需要VAV2和网格蛋白介导的内吞作用。此外,促进细胞迁移的Rho家族GTPase Rac1和VAV2的主要底物也依赖于网格蛋白的持续激活。内源性荧光标记的Rac1定位于含有egfr的内体。总之,我们的研究结果表明,通过EGFR-VAV2-Rac1途径的信号传导在内体中持续存在,并且这种内体信号传导是egfr驱动的细胞迁移所必需的。
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来源期刊
Journal of cell science
Journal of cell science 生物-细胞生物学
CiteScore
7.30
自引率
2.50%
发文量
393
审稿时长
1.4 months
期刊介绍: Journal of Cell Science publishes cutting-edge science, encompassing all aspects of cell biology.
期刊最新文献
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