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Myocilin Is a Modulator of Wnt Signaling▿

By Heung-Sun Kwon, Hee-Sheung Lee, Yun Ji, Jeffrey S. Rubin and Stanislav I. Tomarev


It is well documented that mutations in the MYOCILIN gene may lead to juvenile- and adult-onset primary open-angle glaucoma. However, the functions of wild-type myocilin are still not well understood. To study the functions of human myocilin and its two proteolytic fragments, these proteins were expressed in HEK293 cells. Conditioned medium from myocilin-expressing cells, as well as purified myocilin, induced the formation of stress fibers in primary cultures of human trabecular meshwork or NIH 3T3 cells. Stress fiber-inducing activity of myocilin was blocked by antibodies against myocilin, as well as secreted inhibitors of Wnt signaling, secreted Frizzled-related protein 1 (sFRP1) or sFRP3, and β-catenin small interfering RNA. Interaction of myocilin with sFRP1, sFRP3, and several Frizzled receptors was confirmed by immunoprecipitation experiments and by binding of myocilin to the surface of cells expressing cysteine-rich domains of different Frizzled and sFRPs. Treatment of NIH 3T3 cells with myocilin and its fragments induced intracellular redistribution of β-catenin and its accumulation on the cellular membrane but did not induce nuclear accumulation of β-catenin. Overexpression of myocilin in the eye angle tissues of transgenic mice stimulated accumulation of β-catenin in these tissues. Myocilin and Wnt proteins may perform redundant functions in the mammalian eye, since myocilin modulates Wnt signaling by interacting with components of this signaling pathway

Topics: Articles
Publisher: American Society for Microbiology (ASM)
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Provided by: PubMed Central
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