A Novel Mechanism by Which Tissue Transglutaminase Activates Signaling Events That Promote Cell Survival

Boroughs, Lindsey K.; Antonyak, Marc A.; Cerione, Richard A.

doi:10.1074/jbc.m113.464693

Cited by 41 publications

(42 citation statements)

References 39 publications

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“…On the other hand, TG dysfunction leads to tumor formation in various carcinomas (9,10). In contrast to the epidermal TGs, TG2 (tissue TG) is ubiquitously expressed and involved in various biological events (11)(12)(13). The analysis of TG2 knockout mice showed impaired phagocytosis of apoptotic cell material and aberrant wound healing (14).…”

Section: Supporting Informationmentioning

confidence: 99%

Distinct protein expression and activity of transglutaminases found in different epidermal tumors

Karashima

Furumura

Ishii

et al. 2014

Experimental Dermatology

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We investigated protein expression and in situ activity of transglutaminases (TGs) in normal skin and various epidermal neoplasms. In normal skin, TG1 protein expression and TG activity were found at keratinocyte cell membranes in upper epidermis and granular layer, respectively. In seborrhoeic keratosis, TG1 protein was expressed evenly throughout tumors, while TG activity increased in gradient fashion from lower tumor area to cornified layer. In squamous cell carcinoma, TG1 protein was expressed at inner side of cell membranes, whereas TG activity was found in cytoplasm predominantly at horn pearls. In basal cell carcinoma, weak TG activity was found in cytoplasm of all tumor cells without the presence of TG1 protein.Immunoblotting and in situ activity assays using specific substrate peptides confirmed that TG2, but not TG1, contributed to the TG activity. These results suggested that different expression and activation of TGs may contribute to characteristics of the skin tumors.

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Section: Supporting Informationmentioning

confidence: 99%

Distinct protein expression and activity of transglutaminases found in different epidermal tumors

Karashima

Furumura

Ishii

et al. 2014

Experimental Dermatology

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“…The build-up of EGFRs on the surfaces of brain tumor cells promotes their growth and resistance to chemotherapy and radiation. Importantly, tTG can only activate PI 3-kinase and bind c-Cbl when it is capable of binding GTP, thus suggesting that the guanine nucleotide-bound closed conformation is necessary for these effects (10,28).…”

Section: Ttgmentioning

confidence: 99%

Section: Ttgmentioning

confidence: 99%

“…For example, the guanine nucleotide-bound state of tTG has been implicated in cellular transformation (10,27,28). The ectopic expression of wild type (WT) tTG (tTG WT), which would be expected to be bound to GTP, in NIH3T3 fibroblasts protects them from serum starvation-induced apoptosis by stimulating the activation of PI 3-kinase (28). Moreover, our laboratory has also recently shown that GTP-bound tTG contributes to the aggressiveness of high grade brain tumors by binding to the E3 ubiquitin ligase c-Cbl and interfering with its ability to properly target the epidermal growth factor receptor (EGFR) for lysosomal degradation (10).…”

Section: Ttgmentioning

confidence: 99%

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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 multiple functions of the protein depends on its intracellular localization [16]. In particular, when it is localized in the cytosol differentially controls apoptosis in a stimuli-dependent manner, and its transamidating activity is essential for its pro-apoptotic effects [17,18]. In contrast, when TG2 is localized into the nuclear compartment, it phosphorylates different proteins, including retinoblastoma protein (Rb), a substrate for TG2 kinase activity [19].…”

Section: Introductionmentioning

confidence: 99%

Expression of Tissue Transglutaminase in Human Thyroid Cancer Cell Lines: Effect of Novel Enantiopure Triazole Derivatives

Chiacchio¹

2015

Med chem

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A Novel Mechanism by Which Tissue Transglutaminase Activates Signaling Events That Promote Cell Survival

Cited by 41 publications

References 39 publications

Distinct protein expression and activity of transglutaminases found in different epidermal tumors

Distinct protein expression and activity of transglutaminases found in different epidermal tumors

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

Expression of Tissue Transglutaminase in Human Thyroid Cancer Cell Lines: Effect of Novel Enantiopure Triazole Derivatives

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