Department of Physics, Toronto Metropolitan University, Toronto, Ontario, Canada.
Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, Ontario, Canada.
Phys Biol. 2023 Aug 22;20(5). doi: 10.1088/1478-3975/aceecd.
The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology that is stimulated by multiple distinct ligands. Although ligands bind to EGFR while the receptor is exposed on the plasma membrane, EGFR incorporation into endosomes following receptor internalization is an important aspect of EGFR signaling, with EGFR internalization behavior dependent upon the type of ligand bound. We develop quantitative modeling for EGFR recruitment to and internalization from clathrin domains, focusing on how internalization competes with ligand unbinding from EGFR. We develop two model versions: a kinetic model with EGFR behavior described as transitions between discrete states and a spatial model with EGFR diffusion to circular clathrin domains. We find that a combination of spatial and kinetic proofreading leads to enhanced EGFR internalization ratios in comparison to unbinding differences between ligand types. Various stages of the EGFR internalization process, including recruitment to and internalization from clathrin domains, modulate the internalization differences between receptors bound to different ligands. Our results indicate that following ligand binding, EGFR may encounter multiple clathrin domains before successful recruitment and internalization. The quantitative modeling we have developed describes competition between EGFR internalization and ligand unbinding and the resulting proofreading.
表皮生长因子受体（EGFR）是细胞生理学的核心调节剂，受多种不同配体的刺激。虽然配体在 EGFR 暴露于质膜时与 EGFR 结合，但 EGFR 在受体内化后被内吞进入内体是 EGFR 信号传递的一个重要方面，EGFR 的内化行为取决于结合的配体类型。我们建立了定量模型，用于研究 EGFR 从网格蛋白结构域募集和内化，重点关注内化如何与 EGFR 与配体的解结合竞争。我们开发了两种模型版本：一种是具有 EGFR 行为描述为离散状态之间转换的动力学模型，另一种是具有 EGFR 扩散到圆形网格蛋白结构域的空间模型。我们发现，与配体类型之间的解结合差异相比，空间和动力学校对的结合导致 EGFR 内化比例增强。EGFR 内化过程的各个阶段，包括从网格蛋白结构域募集和内化，调节了与不同配体结合的受体之间的内化差异。我们的结果表明，在配体结合后，EGFR 可能在成功募集和内化之前遇到多个网格蛋白结构域。我们开发的定量模型描述了 EGFR 内化和配体解结合之间的竞争以及由此产生的校对。
