Transglutaminase 2 facilitates or ameliorates HIF signaling and ischemic cell death depending on its conformation and localization

Gundemir, Soner; Colak, Gozde; Feola, Julianne; Blouin, Richard; Johnson, Gail V.W.

doi:10.1016/j.bbamcr.2012.10.011

Cited by 36 publications

(41 citation statements)

References 64 publications

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“…However, potential effects of TG2 on signaling pathways are relatively understudied. Previous reports have shown effects of TG2 on serotonylation of the small GTPases RhoA and Rab [8]; while others have proposed modulatory effects of TG2 on EGF, PDGF, HIF and NFkB pathways [9, 10, 14, 28]. TG2 modulation of serotonin-mediated RhoA signaling in pulmonary vascular cells has been reported by another group, although this was in the context of supra-physiologic levels of serotonin [15].…”

Section: Discussionmentioning

confidence: 98%

“…It may also modify proteins with monoamines; when the amine is 5-HT the process is referred to as serotonylation [8]. It has become increasingly recognized that TG2-mediated changes modulate a variety of cellular responses such as cytoskeletal reorganization, cell adhesion, cell signaling and survival [9–11], and subsequently impact various pathophysiologic responses involved in inflammation and cancer [12]. For example, TG2 is an essential participant in the epidermal growth factor-stimulated signaling pathway leading to cancer cell migration and invasion [13, 14].…”

Section: Introductionmentioning

confidence: 99%

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Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

Penumatsa¹,

Abualkhair²,

Lin³

et al. 2014

Cellular Signalling

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Tissue transglutaminase 2 (TG2) is a multifunctional enzyme that cross-links proteins with monoamines such as serotonin (5-hydroxytryptamine, 5-HT) via a transglutamidation reaction, and is associated with pathophysiologic vascular responses. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PASMC) that has been linked to the pulmonary vascular remodeling underlying pulmonary hypertension development. We previously reported that 5-HT-induced PASMC proliferation is inhibited by the TG2 inhibitor monodansylcadaverine (MDC); however, the mechanisms are poorly understood. In the present study we hypothesized that TG2 contributes to 5-HT-induced signaling pathways of PASMC. Pre-treatment of bovine distal PASMC with varying concentrations of the inhibitor MDC led to differential inhibition of 5-HT-stimulated AKT and ROCK activation, while p-P38 was unaffected. Concentration response studies showed significant inhibition of AKT activation at 50 μM MDC, along with inhibition of the AKT downstream targets mTOR, p-S6 Kinase and p-S6. Furthermore, TG2 depletion by siRNA led to reduced 5-HT-induced AKT activation. Immunoprecipitation studies showed that 5-HT treatment led to increased levels of serotonylated AKT and increased TG2-AKT complex formations which were inhibited by MDC. Overexpression of TG2 point mutant cDNAs in PASMC showed that the TG2 C277V transamidation mutant blunted 5-HT-induced AKT activation and 5-HT-induced PASMC mitogenesis. Finally, 5-HT-induced AKT activation was blunted in SERT genetic knock-out rat cells, but not in their wild-type counterpart. The SERT inhibitor imipramine similarly blocked AKT activation. These results indicate that TG2 contributes to 5-HT-induced distal PASMC proliferation via promotion of AKT signaling, likely via its serotonylation. Taken together, these results provide new insight into how TG2 may participate in vascular smooth muscle remodeling.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

Penumatsa¹,

Abualkhair²,

Lin³

et al. 2014

Cellular Signalling

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“…as an outcome of a point-mutation), it has an adverse effect on cells (22,27,29). Perhaps the best example of this came from a study that showed ectopically expressing a GTP binding-defective form of tTG (tTG R580K), which presumably adopts an open conformation, induces normal as well as cancer cell lines to undergo apoptosis (22).…”

Section: Ttgmentioning

confidence: 99%

The Different Conformational States of Tissue Transglutaminase Have Opposing Affects on Cell Viability

Singh

Zhang

et al. 2016

Journal of Biological Chemistry

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Tissue transglutaminase (tTG) is an acyltransferase/GTPbinding protein that contributes to the development of various diseases. In human cancer cells, tTG activates signaling pathways that promote cell growth and survival, whereas in other disorders (i.e. neurodegeneration), overexpression of tTG enhances cell death. Therefore, it is important to understand how tTG is differentially regulated and functioning to promote diametrically distinct cellular outcomes. Previous structural studies revealed that tTG adopts either a nucleotide-bound closed conformation or a transamidation-competent open conformation. Here we provide evidence showing that these different conformational states determine whether tTG promotes, or is detrimental to, cell survival, with the open conformation of the protein being responsible for inducing cell death. First, we demonstrate that a nucleotide binding-defective form of tTG, which has previously been shown to induce cell death, assumes an open conformation in solution as assessed by an enhanced sensitivity to trypsin digestion and by small angle x-ray scattering (SAXS) analysis. We next identify two pairs of intramolecular hydrogen bonds that, based on existing x-ray structures, are predicted to form between the most C-terminal ␤-barrel domain and the catalytic core domain of tTG. By disrupting these hydrogen bonds, we are able to generate forms of tTG that constitutively assume an open conformation and induce apoptosis. These findings provide important insights into how tTG participates in the pathogenesis of neurodegenerative diseases, particularly with regard to the actions of a C-terminal truncated form of tTG (TG-Short) that has been linked to such disorders and induces apoptosis by assuming an open-like conformation.

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“…The transamidase activity of TG2 leads to the incorporation/ deamidation of primary amines and of protein crosslinking by catalyzing the formation of isopeptide bond at the level of the amino groups of peptide-bound glutamine and lysine. 11 In addition to its transamidase activity, TG2 has been shown to act as GTPase involved in the intracellular G protein signalling (as Gha) at the level of adrenergic receptor. 12 More recently, TG2 has also been reported to possess intracellular serine/threonine kinase and protein disulphide isomerase activity (PDI).…”

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confidence: 99%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.

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Transglutaminase 2 facilitates or ameliorates HIF signaling and ischemic cell death depending on its conformation and localization

Cited by 36 publications

References 64 publications

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells

The Different Conformational States of Tissue Transglutaminase Have Opposing Affects on Cell Viability

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

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