Antagonizing c-Cbl enhances EGFR-dependent corneal epithelial homeostasis.
Antagonizing c-Cbl enhances EGFR-dependent corneal epithelial homeostasis.
复制标题
拮抗 c-Cbl 可增强 EGFR 依赖性角膜上皮稳态。
DOI：
10.1167/iovs.14-14133
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发表时间：
2014
影响因子：
4.4
通讯作者：
Ceresa,BrianP
中科院分区：
文献类型：
--
作者：
Rush,JamieS;Boeving,MichaelA;Berry,WilliamL;Ceresa,BrianP
Purpose.: In many cell types, the E3 ubiquitin ligase, c-Cbl, induces ligand-dependent ubiquitylation of the epidermal growth factor receptor (EGFR) and targets the receptor for lysosomal degradation. The goal of this study was to determine whether c-Cbl is a negative regulator of EGFR in the corneal epithelium and if it can be inhibited to promote corneal epithelial homeostasis.Methods.: Expression and activity of c-Cbl were blocked in immortalized human corneal epithelial cells (hTCEpi) using RNAi and pharmacological agents ([4-amino-5-(4-methylphenyl)-7-(t-butyl) pyrazolo-d-3, 4-pyrimidine] or PP1). Following c-Cbl inhibition, cells were assessed for ligand-dependent receptor ubiquitylation, receptor phosphorylation, and in vitro wound healing. Subsequent experiments used PP1 in hTCEpi cells and monitored in vivo murine corneal epithelial wound healing.Results.: Knockdown and inhibition of c-Cbl decreased ligand-dependent ubiquitylation of the EGFR and prolonged receptor activity as measured by tyrosine phosphorylation. Further, these treatments also increased the extent of ligand-dependent corneal epithelial wound healing in vitro and in vivo.Conclusion.: Manipulating the duration of EGFR activity can enhance the rate of restoration of the corneal epithelial layer. Based on our findings, c-Cbl is a new therapeutic target to enhance EGFR-mediated corneal epithelial homeostasis that bypasses the limitations of previous approaches.
