title: TGF-β induces phosphorylation of phosphatase and tensin homolog: implications for fibrosis of the trabecular meshwork tissue in glaucoma.
abstract: Fundamental cell signaling mechanisms that regulate dynamic remodeling of the extracellular matrix (ECM) in mechanically loaded tissues are not yet clearly understood. Trabecular meshwork (TM) tissue in the eye is under constant mechanical stress and continuous remodeling of ECM is crucial to maintain normal aqueous humor drainage and intraocular pressure (IOP). However, excessive ECM remodeling can cause fibrosis of the TM as in primary open-angle glaucoma (POAG) patients, and is characterized by increased resistance to aqueous humor drainage, elevated IOP, optic nerve degeneration and blindness. Increased levels of active transforming growth factor-β2 (TGF-β2) in the aqueous humor is the main cause of fibrosis of TM in POAG patients. Herein, we report a novel finding that, in TM cells, TGF-β-induced increase in collagen expression is associated with phosphorylation of phosphatase and tensin homolog (PTEN) at residues Ser380/Thr382/383. Exogenous overexpression of a mutated form of PTEN with enhanced phosphatase activity prevented the TGF-β-induced collagen expression by TM cells. We propose that rapid alteration of PTEN activity through changes in its phosphorylation status could uniquely regulate the continuous remodeling of ECM in the normal TM. Modulating PTEN activity may have high therapeutic potential to alleviating the fibrosis of TM in POAG patients.
authors.affiliation: Department of Ophthalmology, University of Western Ontario, London, ON, N6A 4V2, Canada.|Pathology and Laboratory Medicine, University of Western Ontario, London, ON, N6A 5C1, Canada.
authors.forename: Nikoleta
authors.initials: N
authors.lastname: Tellios
authors.affiliation: Department of Ophthalmology, University of Western Ontario, London, ON, N6A 4V2, Canada.|Department of Anesthesia & Perioperative Medicine, University of Western Ontario, London, ON, N6A 5A5, Canada.
authors.forename: Jillian C
authors.initials: JC
authors.lastname: Belrose
authors.affiliation: Department of Ophthalmology, University of Western Ontario, London, ON, N6A 4V2, Canada.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Tokarewicz
authors.affiliation: Department of Ophthalmology, University of Western Ontario, London, ON, N6A 4V2, Canada.|Pathology and Laboratory Medicine, University of Western Ontario, London, ON, N6A 5C1, Canada.|Lawson Health Research Institute, St. Joseph's Health Care, London, ON, N6A 4V2, Canada.
authors.forename: Cindy
authors.initials: C
authors.lastname: Hutnik
authors.affiliation: Lawson Health Research Institute, St. Joseph's Health Care, London, ON, N6A 4V2, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.affiliation: Department of Ophthalmology, University of Western Ontario, London, ON, N6A 4V2, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Motolko
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Miho
authors.initials: M
authors.lastname: Iijima
authors.affiliation: Department of Ophthalmology, University of Western Ontario, London, ON, N6A 4V2, Canada. sparapur@uwo.ca.|Pathology and Laboratory Medicine, University of Western Ontario, London, ON, N6A 5C1, Canada. sparapur@uwo.ca.|Lawson Health Research Institute, St. Joseph's Health Care, London, ON, N6A 4V2, Canada. sparapur@uwo.ca.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Parapuram
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005902:Glaucoma, Open-Angle / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D014129:Trabecular Meshwork / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016212:Transforming Growth Factor beta; D003094:Collagen; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human