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Focal adhesion kinase family is involved in matrix contraction by transdifferentiated Müller cells

Rintaro Tsukahara1, Kazuhiko Umazume2, Kevin McDonald3

  • 1Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E Muhammad Ali Blvd., Louisville, KY 40202, USA; Department of Ophthalmology, Tokyo Medical University, Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki-gun, Ibaraki 300-0332, Japan.

Experimental Eye Research
|August 19, 2017
PubMed

Insights

Dasatinib and FAK/PYK2 inhibitors reduce matrix contraction in epiretinal membranes by targeting Müller cells. This study identifies focal adhesion kinase family members and Hic-5 as key players in this process.

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Biochemistry

Background:

  • Transdifferentiated Müller cells with fibroblastic/myofibroblastic phenotypes contribute to epiretinal membrane (ERM) formation and contraction.
  • Dasatinib, a dual Src-family and Abl kinase inhibitor, previously showed efficacy in preventing matrix contraction by these cells.

Purpose of the Study:

  • To investigate molecules downstream of dasatinib's primary targets involved in matrix contraction.
  • To elucidate the role of focal adhesion kinase (FAK) family members and Hic-5 in Müller cell-mediated matrix contraction.

Main Methods:

  • Utilized dasatinib and specific inhibitors (PF431396, PF573228) targeting FAK family kinases (FAK, PYK2).
  • Assessed the impact of these inhibitors on matrix contraction by transdifferentiated Müller cells.
  • Measured tyrosine phosphorylation levels of FAK, PYK2, and Hic-5.

Main Results:

  • Dasatinib significantly reduced tyrosine phosphorylation of FAK and PYK2.
  • Inhibitors PF431396 (FAK/PYK2) and PF573228 (FAK-specific) markedly reduced matrix contraction.
  • Dasatinib and PF431396 decreased Hic-5 phosphorylation, indicating its downstream position.

Conclusions:

  • FAK family members (FAK and PYK2) are crucial mediators of matrix contraction in transdifferentiated Müller cells.
  • Hic-5 is implicated as a downstream signaling molecule in the FAK-mediated pathway contributing to matrix contraction.

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