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Src mediates TGF‐β‐induced intraocular pressure elevation in glaucoma
Author(s) -
Tsukamoto Teruhisa,
Kajiwara Kentaro,
Nada Shigeyuki,
Okada Masato
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27044
Subject(s) - trabecular meshwork , extracellular matrix , proto oncogene tyrosine protein kinase src , glaucoma , focal adhesion , microbiology and biotechnology , downregulation and upregulation , transforming growth factor , cancer research , signal transduction , chemistry , medicine , biology , ophthalmology , biochemistry , gene
Glaucoma, a progressive and irreversible optic neuropathy, is one of the leading causes of vision impairment worldwide. Elevation of intraocular pressure (IOP) due to transforming growth factor‐β (TGF‐β)‐induced dysfunction of the trabecular meshwork is a risk factor for glaucoma, but the underlying molecular mechanisms remain elusive. Here, we show that Src kinase is involved in TGF‐β‐induced IOP elevation. We observed that dasatinib, a potent Src inhibitor, suppressed TGF‐β2‐induced IOP in rat eyes. Mechanistic analyses in human trabecular meshwork cells showed that TGF‐β2 activated Src signaling and concomitantly increased cytoskeletal remodeling, cell adhesion, and extracellular matrix (ECM) accumulation. Src was activated via TGF‐β2‐induced upregulation of the Src scaffolding protein CasL, which mediates the assembly of focal adhesions, cytoskeletal remodeling, and ECM deposition. Activation of Src suppressed the expression of tissue plasminogen activator, thereby attenuating ECM degradation. Furthermore, the Src inhibitor ameliorated TGF‐β2‐induced changes in the contractile and adhesive characteristics of trabecular meshwork cells, and ECM deposition. These findings underscore the crucial role of Src activity in TGF‐β‐induced IOP elevation and identify Src signaling as a potential therapeutic target in glaucoma.