Intricate signaling systems are required to maintain homeostasis and promote differentiation in the epidermis. Receptor tyrosine kinases are central in orchestrating these systems in epidermal keratinocytes. In particular, EPHA2 and EGFR transduce distinct signals to dictate keratinocyte fate, yet how these cell communication networks are integrated has not been investigated. Our work shows that loss of EPHA2 impairs keratinocyte stratification, differentiation, and barrier function. To determine the mechanism of this dysfunction, we drew from our proteomics data of potential EPHA2 interacting proteins. We identified EGFR as a high-ranking EPHA2 interactor and subsequently validated this interaction. We found that when EPHA2 is reduced, EGFR activation and downstream signaling are intensified and sustained. Evidence indicates that prolonged SRC association contributes to the increase in EGFR signaling. We show that hyperactive EGFR signaling underlies the differentiation defect caused by EPHA2 knockdown because EGFR inhibition restores differentiation in EPHA2-deficient 3-dimensional skin organoids. Our data implicate a mechanism whereby EPHA2 restrains EGFR signaling, allowing for fine tuning in the processes of terminal differentiation and barrier formation. Taken together, we purport that crosstalk between receptor tyrosine kinases EPHA2 and EGFR is critical for epidermal differentiation.

中文翻译：

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受体酪氨酸激酶 EPHA2 通过调节 EGFR 信号传导驱动表皮分化

需要复杂的信号系统来维持稳态并促进表皮分化。受体酪氨酸激酶在表皮角质形成细胞中协调这些系统中发挥着核心作用。特别是，EPHA2 和 EGFR 转导不同的信号来决定角质形成细胞的命运，但这些细胞通信网络如何整合尚未得到研究。我们的工作表明，EPHA2 的缺失会损害角质形成细胞的分层、分化和屏障功能。为了确定这种功能障碍的机制，我们利用了潜在 EPHA2 相互作用蛋白的蛋白质组学数据。我们将 EGFR 确定为高级 EPHA2 相互作用因子，并随后验证了这种相互作用。我们发现，当 EPHA2 减少时，EGFR 激活和下游信号传导会增强并持续。有证据表明，延长 SRC 关联有助于增强 EGFR 信号传导。我们发现，过度活跃的 EGFR 信号传导是 EPHA2 敲低引起的分化缺陷的基础，因为 EGFR 抑制可恢复 EPHA2 缺陷的 3 维皮肤类器官的分化。我们的数据暗示了 EPHA2 抑制 EGFR 信号传导的机制，从而允许在终末分化和屏障形成过程中进行微调。综上所述，我们认为受体酪氨酸激酶 EPHA2 和 EGFR 之间的串扰对于表皮分化至关重要。