TGF-β induces phosphorylation of phosphatase and tensin homolog: implications for fibrosis of the trabecular meshwork tissue in glaucoma.
TGF-β induces phosphorylation of phosphatase and tensin homolog: implications for fibrosis of the trabecular meshwork tissue in glaucoma.
复制标题
TGF-β 诱导磷酸酶和张力蛋白同源物的磷酸化：对青光眼小梁网组织纤维化的影响。
DOI：
10.1038/s41598-017-00845-x
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发表时间：
2017
影响因子：
4.6
通讯作者：
Parapuram,SunilK
中科院分区：
文献类型：
--
作者：
Tellios,Nikoleta;Belrose,JillianC;Tokarewicz,AlexanderC;Hutnik,Cindy;Liu,Hong;Leask,Andrew;Motolko,Michael;Iijima,Miho;Parapuram,SunilK
调节机械负荷组织中细胞外基质（ECM）动态重塑的基本细胞信号传导机制尚未清楚。眼内的小梁网（TM）组织处于恒定的机械应力下，ECM的持续重塑对于维持正常的房水引流和眼内压（IOP）至关重要。然而，过度的ECM重塑可导致TM纤维化，如在原发性开角型青光眼（POAG）患者中，并且其特征在于对房水引流的阻力增加、IOP升高、视神经变性和失明。POAG患者房水中活性转化生长因子-β2（TGF-β2）水平升高是导致TM纤维化的主要原因。在此，我们报告了一个新的发现，在TM细胞中，TGF-β诱导的胶原蛋白表达增加与磷酸酶和张力蛋白同源物（PTEN）在残基Ser 380/Thr 382/383的磷酸化有关。具有增强的磷酸酶活性的突变形式的PTEN的外源性过表达阻止了TM细胞的TGF-β诱导的胶原蛋白表达。我们认为，通过改变其磷酸化状态，快速改变PTEN活性可以独特地调节正常TM中ECM的持续重塑。调节PTEN活性可能对缓解POAG患者TM纤维化具有很高的治疗潜力。
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.