title: Myocilin, a glaucoma-associated protein, promotes cell migration through activation of integrin-focal adhesion kinase-serine/threonine kinase signaling pathway.
abstract: The MYOCILIN gene encodes a secreted glycoprotein which is highly expressed in eye drainage structures. Mutations in this gene may lead to juvenile open-angle glaucoma and adult onset primary open-angle glaucoma, one of the leading causes of irreversible blindness in the world. Functions of wild-type myocilin are still unclear. We have recently demonstrated that myocilin is a modulator of Wnt signaling and may affect actin cytoskeleton organization. Here we report that myocilin and its naturally occurring proteolytic fragments, similar to Wnt3a, are able to stimulate trabecular meshwork, NIH3T3, and FHL124 cell migration with the N-terminal proteolytic fragment of myocilin lacking the olfactomedin domain producing the highest stimulatory effect. Stimulation of cell migration occurs through activation of the integrin-focal adhesion kinase (FAK)-serine/threonine kinase (AKT) signaling pathway. Inhibition of FAK by siRNA reduced the stimulatory action of myocilin by threefold. Activation of several components of this signaling pathway was also demonstrated in the eyes of transgenic mice expressing elevated levels of myocilin in the eye drainage structures. These data extend the similarities between actions of myocilin and Wnt proteins acting through a β-catenin-independent mechanism. The modification of the migratory ability of cells by myocilin may play a role in normal functioning of the eye anterior segment and its pathology including glaucoma.
authors.affiliation: Molecular Mechanisms of Glaucoma Section, Laboratory of Molecular and Developmental Biology, National Eye Institute, NIH, Bethesda, Maryland 20892-9303, USA.
authors.forename: Heung Sun
authors.initials: HS
authors.lastname: Kwon
authors.forename: Stanislav I
authors.initials: SI
authors.lastname: Tomarev
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014129:Trabecular Meshwork / Q000187:drug effects / Q000201:enzymology*; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D051417:Focal Adhesion Kinase 1; D006023:Glycoproteins; D016023:Integrins; D010446:Peptide Fragments; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D000099179:Myocilin; C555510:WNT3A protein, human; C555511:Wnt3a protein, mouse; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse