School of Optometry and Vision Science Program, Indiana University, Bloomington, IN 47405, USA.
Aging (Albany NY). 2024 Oct 25;16(20):13039-13075. doi: 10.18632/aging.206144.
Disruption of Eph-ephrin bidirectional signaling leads to human congenital and age-related cataracts, but the mechanisms for these opacities in the eye lens remain unclear. Eph receptors bind to ephrin ligands on neighboring cells to induce canonical ligand-mediated signaling. The EphA2 receptor also signals non-canonically without ligand binding in cancerous cells, leading to epithelial-to-mesenchymal transition (EMT). We have previously shown that the receptor EphA2 and the ligand ephrin-A5 have diverse functions in maintaining lens transparency in mice. Loss of ephrin-A5 leads to anterior cataracts due to EMT. Surprisingly, both canonical and non-canonical EphA2 activation are present in normal wild-type lenses and in the ephrin-A5 knockout lenses. Canonical EphA2 signaling is localized exclusively to lens epithelial cells and does not change with age. Non-canonical EphA2 signaling is in both epithelial and fiber cells and increases significantly with age. We hypothesize that canonical ligand-dependent EphA2 signaling is required for the morphogenesis and organization of hexagonal equatorial epithelial cells while non-canonical ligand-independent EphA2 signaling is needed for complex membrane interdigitations that change during fiber cell differentiation and maturation. This is the first demonstration of non-canonical EphA2 activation in a non-cancerous tissue or cell and suggests a possible physiological function for ligand-independent EphA2 signaling.
Eph-ephrin 双向信号的中断会导致人类先天性和年龄相关性白内障，但眼睛晶状体这些混浊的机制仍不清楚。Eph 受体与相邻细胞上的 Ephrin 配体结合，诱导经典配体介导的信号转导。EphA2 受体在癌细胞中也无需配体结合即可进行非经典信号转导，导致上皮-间质转化（EMT）。我们之前已经表明，受体 EphA2 和配体 Ephrin-A5 在维持小鼠晶状体透明性方面具有多种功能。Ephrin-A5 的缺失会导致 EMT 引起的前白内障。令人惊讶的是，经典和非经典 EphA2 激活都存在于正常野生型晶状体和 Ephrin-A5 敲除晶状体中。经典 EphA2 信号转导仅局限于晶状体上皮细胞，并且不会随年龄而变化。非经典 EphA2 信号转导存在于上皮细胞和纤维细胞中，并且随着年龄的增长而显著增加。我们假设，经典配体依赖性 EphA2 信号转导对于六角形赤道上皮细胞的形态发生和组织至关重要，而非经典配体非依赖性 EphA2 信号转导对于纤维细胞分化和成熟过程中发生变化的复杂膜内陷是必需的。这是首次在非癌性组织或细胞中证明非经典 EphA2 激活，并提示配体非依赖性 EphA2 信号转导可能具有生理功能。
