Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells

Peotter, Jennifer L.; Phillips, J.; Tong, Tiegang; Dimeo, Kaylee D.; González, José M.; Peters, Donna M.

doi:10.1016/j.yexcr.2016.08.009

Cited by 21 publications

(18 citation statements)

References 41 publications

(69 reference statements)

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“… 56 It is well established that TM cells have phagocytic properties. 57 – 70 Briefly, a single culture of TM cells was established from the B6;129S1-Bambi tm1Jian /J mouse strain by dissecting TM rings from eight eyes. TM rings were placed in collagenase at 37°C for 2 hours.…”

Section: Methodsmentioning

confidence: 99%

BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

Hernandez

Millar

Curry

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeThe trabecular meshwork (TM) has an important role in the regulation of aqueous humor outflow and IOP. Regulation of the extracellular matrix (ECM) by TGFβ2 has been studied extensively. Bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI) has been shown to inhibit or modulate TGFβ2 signaling. We investigate the role of TGFβ2 and BAMBI in the regulation of TM ECM and ocular hypertension.MethodsMouse TM (MTM) cells were isolated from B6;129S1-Bambitm1Jian/J flox mice, characterized for TGFβ2 and dexamethasone (DEX)–induced expression of fibronectin, collagen-1, collagen-4, laminin, α-smooth muscle actin, cross-linked actin networks (CLANs) formation, and DEX-induced myocilin (MYOC) expression. MTM cells were transduced with Ad5.GFP to identify transduction efficiency. MTM cells and mouse eyes were transduced with Ad5.Null, Ad5.Cre, Ad5.TGFβ2, or Ad5.TGFβ2 + Ad5.Cre to evaluate the effect on ECM production, IOP, and outflow facility.ResultsMTM cells express TM markers and respond to DEX and TGFβ2. Ad5.GFP at 100 MOI had the highest transduction efficiency. Bambi knockdown by Ad5.Cre and Ad5.TGFβ2 increased fibronectin, collagen-1, and collagen-4 in TM cells in culture and tissue. Ad5.Cre, Ad5.TGFβ2, and Ad5.TGFβ2 + Ad5.Cre each significantly induced ocular hypertension and lowered aqueous humor outflow facility in transduced eyes.ConclusionsWe show for the first time to our knowledge that knockdown of Bambi alters ECM expression in cultured cells and mouse TM, reduces outflow facility, and causes ocular hypertension. These data provide a novel insight into the development of glaucomatous TM damage and identify BAMBI as an important regulator of TM ECM and ocular hypertension.

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Section: Methodsmentioning

confidence: 99%

BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

Hernandez

Millar

Curry

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Peotter and associates [37] have recently assessed potential roles of Tiam1 and Vav2 in the regulation of Rac1-mediated phagocytosis in human trabecular meshwork [TM] cells. Using pharmacological and molecular biological approaches they demonstrated that αvβ5 integrin/FAK-mediated phogocytosis in these cells is mediated by Rac1.…”

Section: Do Tiam1 and Vav2 Work Together To Facilitate Rac1-mediamentioning

confidence: 99%

“…These studies have also identified ELMO2, RhoG and ILK as upstream regulators of Rac1 activation. Based on these observations, the authors concluded that Tiam1, but not Vav2, plays key regulatory roles in promoting Rac1-mediated phagocytosis in TM cells [37]. …”

Section: Do Tiam1 and Vav2 Work Together To Facilitate Rac1-mediamentioning

confidence: 99%

Tiam1/Vav2-Rac1 axis: A tug-of-war between islet function and dysfunction

Kowluru

2017

Biochemical Pharmacology

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Glucose-stimulated insulin secretion [GSIS] from the islet β-cell involves a well-orchestrated interplay between metabolic and cationic events. It is well established that intracellular generation of adenine and guanine nucleotide triphosphates [e.g., ATP and GTP] represents one of the requisite signaling steps in GSIS. The small molecular mass GTP-binding proteins [G-proteins; e.g., Rac1 and Cdc42] have been shown to regulate islet β-cell function including actin cytoskeletal remodeling and fusion of insulin granules with the plasma membrane for GSIS to occur. In this context, several regulatory factors for these G-proteins have been identified in the pancreatic β-cell; these include guanine nucleotide exchange factors [GEFs] and guanine nucleotide dissociation inhibitors [GDI]. Recent pharmacological and molecular biological evidence identified Tiam1 and Vav2 as GEFs for Rac1 in promoting physiological insulin secretion. Paradoxically, emerging evidence in multiple cell types, including the islet β-cell, suggests key roles for Rac1 in the onset of cellular dysfunction under conditions of metabolic stress and diabetes. Furthermore, functional inactivation of either Tiam1 or Vav2 appears to attenuate sustained activation of Rac1 and its downstream signaling events [activation of stress kinases] under conditions of metabolic stress. Together, these findings suggest both “friendly” and “non-friendly” roles for Tiam1/Vav2-Rac1 signaling axis in islet β-cell in health and diabetes. Our current understanding of the field and the knowledge gaps that exist in this area of islet biology are heighted herein. Furthermore, potential caveats in the specificity and selectivity of pharmacological inhibitors that are available currently are discussed in this Commentary.

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“…There is an insufficient quantity of pigment in the TM to cause a simple physical outflow obstruction; 7 yet, relatively low amounts of pigment can induce a hypertensive phenotype in ex vivo perfusion cultures. [8][9][10] Additionally, microarray expression analysis suggests a central role for ROCK and IGF-1 8 in the onset of PG.…”

Section: Introductionmentioning

confidence: 99%

Impact of Pigment Dispersion on Trabecular Meshwork Cells

Wang

Dang

Loewen

et al. 2018

Preprint

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Purpose: To investigate the effect of pigment dispersion on trabecular meshwork (TM) cells. Methods: Porcine TM cells from ab interno trabeculectomy specimens were exposed to pigment dispersion, then analyzed for changes in morphology, immunostaining, and ultrastructure. Their abilities to phagocytose, migrate, and contract were quantified. An expression microarray, using 23,937 probes, and a pathway analysis were performed. Results: TM cells readily phagocytosed pigment granules. Pigment induced stress fiber formation (pigment (P): 60.1 ± 0.3%, n = 10, control (C): 38.4 ± 2.5%, n = 11, P < 0.001) and contraction at 24 hours onward (P < 0.01). Phagocytosis declined (P: 68.7 ± 1.3%, C: 37.0 ± 1.1%, n = 3, P < 0.001) and migration was reduced after 6 hours (P: 28.0.1 ± 2.3, n = 12, C: 40.6 ± 3.3, n = 13, P < 0.01). Microarray analysis revealed that Rho, IGF-1, and TGFβ signaling cascades were central to these responses. Conclusions: TM cell exposure to pigment dispersion resulted in reduced phagocytosis and migration, as well as increased stress fiber formation and cell contraction. The Rho signaling pathway played a central and early role, suggesting that its inhibitors could be used as a specific intervention in treatment of pigmentary glaucoma.

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Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells

Cited by 21 publications

References 41 publications

BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

BMP and Activin Membrane Bound Inhibitor Regulates the Extracellular Matrix in the Trabecular Meshwork

Tiam1/Vav2-Rac1 axis: A tug-of-war between islet function and dysfunction

Impact of Pigment Dispersion on Trabecular Meshwork Cells

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