Extracellular transglutaminase 2 has a role in cell adhesion, whereas intracellular transglutaminase 2 is involved in regulation of endothelial cell proliferation and apoptosis

Nadalutti, Cristina A.; Viiri, Keijo; Kaukinen, Katri; Mäki, Markku; Lindfors, Katri

doi:10.1111/j.1365-2184.2010.00716.x

Cited by 39 publications

(28 citation statements)

References 34 publications

(47 reference statements)

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“…In a recent study, knockdown of TG2 by siRNA in endothelial cells decreased proliferation, cell adhesion and increased cell death (Nadalutti et al, 2011). Considering that TG2 is ablated in all the cells in TG −/− mice, we performed macrovasculature and microvasculature analysis to determine if there were any changes in the brain vasculature due to the absence of TG2.…”

Section: Resultsmentioning

confidence: 99%

Complete transglutaminase 2 ablation results in reduced stroke volumes and astrocytes that exhibit increased survival in response to ischemia

Colak

Johnson

2012

Neurobiology of Disease

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Transglutaminase 2 (TG2) is a very multifunctional protein that is ubiquitously expressed in the body. It is a Ca2+-dependent transamidating enzyme, a GTPase, as well as a scaffolding protein. TG2 is the predominant form of transglutaminase expressed in the mammalian nervous system. Previously, it was shown that TG2 can affect both cell death and cell survival mechanisms depending on the cell type and the stressor. In the case of ischemic stress, TG2 was previously shown to play a protective role in the models used. For example in hTG2 transgenic mice, where TG2 is overexpressed only in neurons, middle cerebral artery ligation (MCAL) resulted in smaller infarct volumes compared to wild type mice. In this study TG2 knock out mice were used to determine how endogenous TG2 affected stroke volumes. Intriguingly, infarct volumes in TG2 knock out mice were significantly smaller compared to wild type mice. As expected, primary neurons isolated from TG2 knock out mice showed decreased viability in response to oxygen-glucose deprivation. However, primary astrocytes that were isolated from TG2 knock out mice were resistant to oxygen-glucose deprivation in situ. Both wild type and knock out neurons were protected against oxygen glucose deprivation when they were co-cultured with astrocytes from TG2 knockout mice. Therefore, the decreased stroke volumes observed in TG2 knock out mice after MCAL, can be correlated with the protective effects of TG2 knock out in astrocytes in response to oxygen glucose deprivation in situ. These findings suggest that neuron-astrocyte crosstalk plays a significant role in mediating ischemic cell death and that TG2 differentially impacts cell survival depending on cell context.

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Section: Resultsmentioning

confidence: 99%

Complete transglutaminase 2 ablation results in reduced stroke volumes and astrocytes that exhibit increased survival in response to ischemia

Colak

Johnson

2012

Neurobiology of Disease

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“…TGase2 is expressed ubiquitously and is implicated in various cellular processes including cell death, proliferation, adhesion, migration, and cytoskeletal reorganization (13)(14)(15). TGase2 is also associated with various diseases, including cardiovascular diseases (16), inflammation (17,18), celiac disease (19,20), neurodegenerative disorders (21,22), and hemorrhagic or ischemic stroke (23).…”

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confidence: 99%

Essential Role of Transglutaminase 2 in Vascular Endothelial Growth Factor–Induced Vascular Leakage in the Retina of Diabetic Mice

et al. 2016

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Diabetic retinopathy is predominantly caused by vascular endothelial growth factor (VEGF)–induced vascular leakage; however, the underlying mechanism is unclear. Here we designed an in vivo transglutaminase (TGase) activity assay in mouse retina and demonstrated that hyperglycemia induced vascular leakage by activating TGase2 in diabetic retina. VEGF elevated TGase2 activity through sequential elevation of intracellular Ca2+ and reactive oxygen species (ROS) concentrations in endothelial cells. The TGase inhibitors cystamine and monodansylcadaverin or TGase2 small interfering RNA (siRNA) prevented VEGF-induced stress fiber formation and vascular endothelial (VE)–cadherin disruption, which play a critical role in modulating endothelial permeability. Intravitreal injection of two TGase inhibitors or TGase2 siRNA successfully inhibited hyperglycemia-induced TGase activation and microvascular leakage in the retinas of diabetic mice. C-peptide or ROS scavengers also inhibited TGase activation in diabetic mouse retinas. The role of TGase2 in VEGF-induced vascular leakage was further supported using diabetic TGase2−/− mice. Thus, our findings suggest that ROS-mediated activation of TGase2 plays a key role in VEGF-induced vascular leakage by stimulating stress fiber formation and VE-cadherin disruption.

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“…Transglutaminase 2 (TG2), 2 the most ubiquitous member of the transglutaminase family, catalyzes post-translational protein cross-linking with the formation of ⑀-(␥-glutamyl)lysine or (␥-glutamyl)polyamine bonds. This transamidating activity of TG2 regulates a variety of biological responses, including cell death, cell adhesion and proliferation, cytoskeletal reorganization, and cell migration and invasion (1)(2)(3).…”

mentioning

confidence: 99%

“…This transamidating activity of TG2 regulates a variety of biological responses, including cell death, cell adhesion and proliferation, cytoskeletal reorganization, and cell migration and invasion (1)(2)(3). Additionally, TG2 is implicated in neurodegenerative diseases, celiac disease, ischemic stroke and cardiovascular diseases, cataractogenesis, diabetes, and cancer (4 -8).…”

mentioning

confidence: 99%

Transglutaminase 2 Promotes Both Caspase-dependent and Caspase-independent Apoptotic Cell Death via the Calpain/Bax Protein Signaling Pathway

Yoo

Lim

Kim

et al. 2012

Journal of Biological Chemistry

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Background: The function of transglutaminase 2 (TG2) in dying cells is ambiguous. Results: TG2 activity facilitates simultaneous caspase-dependent and apoptosis-inducing factor-mediated apoptotic cell death via a calpain/Bax signaling pathway. Conclusion: We demonstrated a new mechanism of apoptotic cell death induced by photodynamic therapy (PDT). Significance: Understanding the function of TG2 as a therapeutic target will contribute to improved cancer treatments using PDT.

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Extracellular transglutaminase 2 has a role in cell adhesion, whereas intracellular transglutaminase 2 is involved in regulation of endothelial cell proliferation and apoptosis

Cited by 39 publications

References 34 publications

Complete transglutaminase 2 ablation results in reduced stroke volumes and astrocytes that exhibit increased survival in response to ischemia

Complete transglutaminase 2 ablation results in reduced stroke volumes and astrocytes that exhibit increased survival in response to ischemia

Essential Role of Transglutaminase 2 in Vascular Endothelial Growth Factor–Induced Vascular Leakage in the Retina of Diabetic Mice

Transglutaminase 2 Promotes Both Caspase-dependent and Caspase-independent Apoptotic Cell Death via the Calpain/Bax Protein Signaling Pathway

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