Rho GTPase and cAMP/Protein Kinase A Signaling Mediates Myocilin-induced Alterations in Cultured Human Trabecular Meshwork Cells

Shen, Xiang; Koga, Toshikatsu; Park, Bum-Chan; SundarRaj, Nirmala; Yue, Beatrice Y.J.T.

doi:10.1074/jbc.m708250200

Cited by 51 publications

(65 citation statements)

References 44 publications

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“…Our findings vary from the results described by Shen et al (69), who reported that overexpression of myocilin in transfected human trabecular meshwork cells induced a loss of stress fibers and focal adhesion. These differences may be due to differences in the level of myocilin expression, the time of cell exposure to myocilin (days versus hours), the sites of myocilin application (intracellular versus extracellular), and the conditions in which the cells were cultivated (serum-containing medium versus serum-free medium).…”

Section: Discussioncontrasting

confidence: 57%

Myocilin Is a Modulator of Wnt Signaling

Kwon

Lee

et al. 2009

Molecular and Cellular Biology

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It is well documented that mutations in the MYOCILINGlaucoma is a leading cause of blindness in the world. Primary open-angle glaucoma is the most common form of glaucoma. It will affect more than 60 million and blind about 4.5 million people worldwide by the year 2010 (62). It is now well established that a genetic component may contribute to glaucoma, and several glaucoma-associated genes have been identified. The first-identified and the most-studied gene is MYOCILIN (MYOC), which is highly expressed in and secreted by the trabecular meshwork (1,19,72,75,77,78), one of the key components of the eye aqueous humor outflow system. Dominant mutations in MYOC may lead to juvenile openangle glaucoma and are found in 3 to 4% of patients with primary open-angle glaucoma (18,19). The encoded protein, myocilin, belongs to a family of glycosylated proteins containing a C-terminal olfactomedin domain (57,90,91). Olfactomedin domain was originally identified in a glycoprotein isolated from the olfactory epithelium of frogs (71) and subsequently was found in a group of proteins forming a family of olfactomedin domaincontaining proteins. The family of olfactomedin domain-containing proteins includes both secreted and membrane-bound proteins that each exhibit a characteristic distribution in different tissues (4,10,27,30,44,51,58,78,79). Most of the glaucomacausing mutations in myocilin are located in the olfactomedin domain (1,2,18,19,24,72).Besides the trabecular meshwork and sclera (1, 77), high levels of MYOC were observed in the ciliary body (1, 13, 39), iris (89), retinal pigment epithelium/choroid (78, 88), and optic nerve (74). Low levels of MYOC expression were detected in several nonocular tissues (75). Myocilin, being a secreted protein, was also found in the aqueous humor, an intraocular fluid responsible for the supply of nutrients and for removal of metabolites from the avascular tissues of the eye anterior segment (63, 65). Some mutations in the MYOC gene lead to the inhibition of mutated myocilin secretion. Secretion of wildtype myocilin also can be reduced or blocked in the presence of mutated myocilin (22,36,52). It has been suggested that the intracellular accumulation of myocilin aggregates is deleterious to the trabecular meshwork cells, resulting in the deterioration of their function and subsequent elevation of intraocular pressure (IOP) (38,49).Although the MYOC gene has been studied for more than 10 years, the functions of myocilin protein are still not well understood (19,75). Biochemical data indicate that myocilin may interact with several intracellular and extracellular matrix proteins (16,37,48,61,73,78), although the biological significance of such interactions is not clear. The absence of openangle glaucoma in an elderly woman homozygous for the Arg46Stop mutation (45), as well as the absence of glaucoma in people hemizygous for MYOC (87), suggests that the loss of functional myocilin is not critical for the development of glaucoma or for normal eye functioning. These observations are supporte...

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Section: Discussioncontrasting

confidence: 57%

Myocilin Is a Modulator of Wnt Signaling

Kwon

Lee

et al. 2009

Molecular and Cellular Biology

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“…Despite the myocilin-GFP secretion in the medium, the nontransfected cells have normal neurites (Figure 1, A and B) and robust actin stress fibers. 45 The lack of uptake may also explain in part why Kroeber et al 46 did not detect any glaucoma phenotype in their transgenic mice overexpressing wild-type myocilin under the control of lens specific ␤B1-crystalline promoter (␤B1-crystallin-MYOC mice) with abundant myocilin secreted into the aqueous humor.…”

Section: Discussionmentioning

confidence: 99%

“…This implies that myocilin may have more of an impact on the cells in the aqueous outflow pathway such as the TM than those in the optic nerve head and the retina such as RGCs, and vice versa in the case of optineurin. Myocilin has previously been shown to affect the actin cytoskeletal structure 45,55 and to lower the mitochondrial membrane potential 56 in human TM cells. The revelation that myocilin also impacts neurite outgrowth in neuronal cells is somewhat surprising.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Myocilin and Optineurin, Two Glaucoma Genes, on Neurite Outgrowth

Koga

Shen

Park

et al. 2010

The American Journal of Pathology

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Myocilin and optineurin are two genes linked to glaucoma , a major blinding disease characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. To investigate the effects of force-expressed wild-type and mutant myocilin and optineurin on neurite outgrowth in neuronal cells , we transiently transfected cells with pEGFP-N1 (mock control) as well as myocilin and optineurin plasmids including pMYOC WT -EGFP, pMYOC P370L -EGFP, pMYOC 1-367 -EGFP, pOPTN WT -EGFP , and pOPTN E50K -EGFP. PC12 cells transfected with pEGFP-N1 produced , as anticipated, long and extensive neuritis on nerve growth factor induction. The neurite length in those cells transfected with myocilin constructs was shortened and the number of neurites was also reduced. A similar inhibitory effect on neurite outgrowth was also elicited by myocilin transfection in RGC5 cells. In contrast , neither transfection of the optineurin constructs pOPTN WT -EGFP and pOPTN E50K -EGFP nor the myocilin and optineurin small-interfering RNA treatments induced significant alterations in neurite outgrowth. Transfection with the wild-type optineurin construct , but not with that of the wild-type myocilin, increased the apoptotic activity in cells. These results demonstrated that the two glaucoma genes , myocilin and optineurin, exhibited differential effects on neurite outgrowth. They may contribute to the development of neurodegenerative glaucoma via distinct mechanisms.

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“…39 For example, cAMP-dependent Protein kinase A induction in cultured human trabecular meshwork cells directly phosphorylated and inactivated RhoA, resulting in stress fiber dissociation. 40 Whether PGE 2 modulates its effects on the podocyte cytoskeleton and adhesion through regulation of Rho GTPase activity or other pathways such as those involving integrin receptor expression or focal adhesion kinase activity remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

A Maladaptive Role for EP4 Receptors in Podocytes

Stitt-Cavanagh¹,

Faour²,

Takami³

et al. 2010

Journal of the American Society of Nephrology

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Inhibition of p38 mitogen-activated protein kinase and cyclooxygenase-2 reduces albuminuria in models of chronic kidney disease marked by podocyte injury. Previously, we identified a feedback loop in podocytes whereby an in vitro surrogate for glomerular capillary pressure (i.e., mechanical stretch) along with prostaglandin E 2 stimulation of its EP4 receptor induced cyclooxygenase-2 in a p38-dependent manner. Here we asked whether stimulation of EP4 receptors would exacerbate glomerulopathies associated with enhanced glomerular capillary pressure. We generated mice with either podocyte-specific overexpression or depletion of the EP4 receptor (EP4 podϩ and EP4 podϪ/Ϫ , respectively). Glomerular prostaglandin E 2 -stimulated cAMP levels were eightfold greater for EP4 podϩ mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were Ͼ50% lower, and prostaglandin E 2 -induced cAMP synthesis was absent in podocytes isolated from EP4 podϪ/Ϫ mice. Non-TG and EP4 podϩ mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (ϩ25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϩ mice (3438 g/mg) was significantly higher than that of non-TG mice (773 g/mg; P Ͻ 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4 podϩ mice was significantly lower than that for non-TG mice (14 versus 67%). In contrast, 6 weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϪ/Ϫ mice (753 g/mg) was significantly lower than that of non-TG mice (2516 g/mg; P Ͻ 0.05). These findings suggest that prostaglandin E 2 , acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.

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Rho GTPase and cAMP/Protein Kinase A Signaling Mediates Myocilin-induced Alterations in Cultured Human Trabecular Meshwork Cells

Cited by 51 publications

References 44 publications

Myocilin Is a Modulator of Wnt Signaling

Myocilin Is a Modulator of Wnt Signaling

Differential Effects of Myocilin and Optineurin, Two Glaucoma Genes, on Neurite Outgrowth

A Maladaptive Role for EP4 Receptors in Podocytes

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