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Invest Ophthalmol Vis Sci. 2012 Feb 23;53(2):936-45. doi: 10.1167/iovs.11-8685. Print 2012 Feb.

EphA2/Ephrin-A1 signaling complexes restrict corneal epithelial cell migration.

Author information

1
Department of Dermatology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA.

Abstract

PURPOSE:

Eph/ephrin signaling proteins are present in the corneal epithelium, where their function remains unknown. The authors examined the role of the EphA2 receptor and ephrin-A1 ligand in human corneal epithelial cell migration.

METHODS:

Immunohistochemical analysis of EphA2 and ephrin-A1 in healthy and diabetic corneas was performed in concert with linear scratch wound healing studies in primary and telomerase-immortalized human corneal epithelial cells. Corneal epithelial cells were exposed to a soluble ephrin-A1-Fc peptide mimetic that targets EphA2 to trigger receptor phosphorylation and subsequent downregulation. Genetic modulation of EphA2 and ephrin-A1 levels was combined with manipulation of Erk1/2 or Akt signaling during wound healing.

RESULTS:

EphA2 was immunolocalized to human corneal epithelial cells in vivo and in vitro. Ephrin-A1 ligand targeting of EphA2 restricted the ability of corneal epithelial cells to seal linear scratch wounds in a manner that was associated with a transient reduction in Erk1/2 and Akt activation state. Ephrin-A1-Fc treatment delayed wound healing independently of Mek-Erk1/2 signaling but was no longer capable of restricting migration after pharmacologic blockade of the PI3K-Akt pathway. Interestingly, ephrin-A1 immunoreactivity was increased in the corneal epithelia of diabetic individuals, mice maintained on a high-fat diet, or cultured corneal epithelial cells exposed to high glucose, which exhibit impaired Akt signaling and slower wound healing responses.

CONCLUSIONS:

EphA2 attenuates corneal epithelial cell migration when stimulated by ephrin-A1 ligand in a manner that involves the suppression of Akt. Elevated levels of ephrin-A1 may contribute to diabetic keratopathies by persistently engaging EphA2 and prohibiting Akt-dependent corneal epithelial repair processes.

PMID:
22247486
PMCID:
PMC3317430
DOI:
10.1167/iovs.11-8685
[Indexed for MEDLINE]
Free PMC Article
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