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Molecular and Cellular Biology, April 2009, p. 2139-2154, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01274-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Myocilin Is a Modulator of Wnt Signaling{triangledown}

Heung-Sun Kwon,1 Hee-Sheung Lee,1 Yun Ji,2 Jeffrey S. Rubin,2 and Stanislav I. Tomarev1*

Section of Molecular Mechanisms of Glaucoma, Laboratory of Molecular and Developmental Biology, National Eye Institute,1 Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-07042

Received 11 August 2008/ Returned for modification 20 October 2008/ Accepted 27 January 2009

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.

* Corresponding author. Mailing address: Molecular Mechanisms of Glaucoma Section, Laboratory of Molecular and Developmental Biology, National Eye Institute, NIH, 5635 Fishers Lane, Rm. 1122, Bethesda, MD 20892-0704. Phone: (301) 496-8524. Fax: (301) 402-0781. E-mail: tomarevs{at}nei.nih.gov

{triangledown} Published ahead of print on 2 February 2009.

Molecular and Cellular Biology, April 2009, p. 2139-2154, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01274-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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