SEARCHOTHERophthalmology, cataract surgery

other·ophthalmology, cataract surgery, preclinical research, biomedical research·PMC10916858

Tonic ErbB signaling underlies TGFβ-induced activation of ERK and is required for lens cell epithelial to myofibroblast transition

Molecular Biology of the Cell · 3 authors, 2 centres

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TL;DR

This preclinical study used primary chick lens epithelial cell cultures to investigate how TGFβ induces myofibroblast differentiation, a process linked to complications after cataract surgery. The central finding is that tonic (constitutive) ErbB signaling is required for TGFβ to activate the ERK pathway, which is essential for this fibrotic transition.

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The study used serum-free primary cultures of chick lens epithelial cells (DCDMLs) as a model to investigate signaling pathways in TGFβ-induced epithelial-to-myofibroblast transition (EMyT). Researchers found that inhibitors of either ErbB or ERK signaling prevented TGFβ from upregulating fibronectin and αSMA, markers of myofibroblast differentiation. TGFβ stimulated ERK phosphorylation within 1.5 hours. A key mechanistic insight was that kinase inhibitors of ErbBs, but not other growth factor receptors, reduced basal phospho-ERK levels, indicating constitutive ErbB activity regulates basal ERK signaling. The proposed model suggests TGFβ-generated reactive oxygen species indirectly amplify ERK signaling downstream of tonically active ErbBs.

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other

SPECIALTY

ophthalmology

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100% · A

ORIGINAL PAPER

PMC10916858

Tonic ErbB signaling underlies TGFβ-induced activation of ERK and is required for lens cell epithelial to myofibroblast transition

Molecular Biology of the Cell

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ABSTRACT

Abstract Fibrosis is a major, but incompletely understood, component of many diseases. The most common vision-disrupting complication of cataract surgery involves differentiation of residual lens cells into myofibroblasts. In serum-free primary cultures of lens epithelial cells (DCDMLs), inhibitors of either ERK or of ErbB signaling prevent TGFβ from upregulating both early (fibronectin) and late (αSMA) markers of myofibroblast differentiation. TGFβ stimulates ERK in DCDMLs within 1.5 h. Kinase inhibitors of ErbBs, but not of several other growth factor receptors in lens cells, reduce phospho ERK to below basal levels in the absence or presence of TGFβ. This effect is attributable to constitutive ErbB activity playing a major role in regulating the basal levels pERK. Additional studies support a model in which TGFβ-generated reactive oxygen species serve to indirectly amplify ERK signaling downstream of tonically active ErbBs to mediate myofibroblast differentiation. ERK activity is in turn essential for expression of ErbB1 and ErbB2, major inducers of ERK signaling. By mechanistically linking TGFβ, ErbB, and ERK signaling to myofibroblast differentiation, our data elucidate a new role for ErbBs in fibrosis and reveal a novel mode by which TGFβ directs lens cell fate.

CITATION EXPORT

Judy K VanSlyke, Bruce A Boswell, Linda S Musil. Tonic ErbB signaling underlies TGFβ-induced activation of ERK and is required for lens cell epithelial to myofibroblast transition. Molecular Biology of the Cell. (2024). https://doi.org/10.1091/mbc.E23-07-0294

AUTHORS

3 · 2 CENTRES

Judy K VanSlyke, Bruce A Boswell, Linda S Musil

aDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon 97239
bUniversity of New Mexico