TGF-β induces phosphorylation of phosphatase and tensin homolog: implications for fibrosis of the trabecular meshwork tissue in glaucoma

被引:35
作者
Tellios, Nikoleta [1 ,2 ]
Belrose, Jillian C. [1 ,3 ]
Tokarewicz, Alexander C. [1 ]
Hutnik, Cindy [1 ,2 ,5 ]
Liu, Hong [5 ]
Leask, Andrew [4 ]
Motolko, Michael [1 ]
Iijima, Miho [6 ]
Parapuram, Sunil K. [1 ,2 ,5 ]
机构
[1] Univ Western Ontario, Dept Ophthalmol, London, ON N6A 4V2, Canada
[2] Univ Western Ontario, Pathol & Lab Med, London, ON N6A 5C1, Canada
[3] Univ Western Ontario, Dept Anesthesia & Perioperat Med, London, ON N6A 5A5, Canada
[4] Univ Western Ontario, Schulich Sch Med & Dent, Dent, London, ON N6A 5C1, Canada
[5] Univ Western Ontario, St Josephs Hlth Care, Lawson Hlth Res Inst, London, ON N6A 4V2, Canada
[6] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA
关键词
GROWTH-FACTOR-BETA; OPEN-ANGLE GLAUCOMA; OPTIC-NERVE DAMAGE; TUMOR-SUPPRESSOR; PTEN EXPRESSION; P38; MAPK; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; ACTIVATION; CELLS;
D O I
10.1038/s41598-017-00845-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-beta 2 (TGF-beta 2) 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-beta 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-beta-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.
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页数:10
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