Increased TG2 Expression Can Result in Induction of Transforming Growth Factor β1, Causing Increased Synthesis and Deposition of Matrix Proteins, Which Can Be Regulated by Nitric Oxide

Telci, Dilek; Collighan, Russell; Başağa, Hüveyda; Griffin, Martin

doi:10.1074/jbc.m109.041806

Cited by 66 publications

(78 citation statements)

References 56 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Turning our attention to assess whether the levels of the fibrotic cytokine TGFb1 were different between the CT26 clones, we found increased levels of TGFb1 in the medium of the active TG2 transfected clone, which could be inhibited by the inclusion of site-directed TG inhibitors in the culture medium. Moreover, addition of exogenous TG2 to the cell cultures of the inactive mutant or the empty vector cells raised the level of active TGFb1 to the level of the clone carrying the active enzyme, thus supporting earlier findings for the involvement of TG2 in TGFb1 activation Telci et al 2009). …”

Section: Discussionsupporting

confidence: 86%

The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26

et al. 2010

Self Cite

View full text Add to dashboard Cite

The multifunctional enzyme tissue transglutaminase (TG2) is reported to both mediate and inhibit tumour progression. To elucidate these different roles of TG2, we established a series of stable-transfected mouse colon carcinoma CT26 cells expressing a catalytically active (wild type) and a transamidating-inactive TG2 (Cys277Ser) mutant. Comparison of the TG2-transfected cells with the empty vector control indicated no differences in cell proliferation, apoptosis and susceptibility to doxorubicin, which correlated with no detectable changes in the activation of the transcription factor NF-jB. TG2-transfected cells showed increased expression of integrin b3, and were more adherent and less migratory on fibronectin than control cells. Direct interaction of TG2 with b3 integrins was demonstrated by immunoprecipitation, suggesting that TG2 acts as a coreceptor for fibronectin with b3 integrins. All cells expressed the same level of TGFb receptors I and II, but only cells transfected with active TG2 had increased levels of TGFb1 and matrix-deposited fibronectin, which could be inhibited by TG2 site-directed inhibitors. Moreover, only cells transfected with active TG2 were capable of inhibiting tumour growth when compared to the empty vector controls. We conclude that in this colon carcinoma model increased levels of active TG2 are unfavourable to tumour growth due to their role in activation of TGFb1 and increased matrix deposition, which in turn favours increased cell adhesion and a lowered migratory and invasive behaviour.

show abstract

Section: Discussionsupporting

confidence: 86%

The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26

et al. 2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although found to protect against disulfide bond formation in our experiments, Ca 2ϩ has been reported to promote inactivation of TG2 through nitrosylation (26). This was also found to be reversible, although it is not clear whether inactivation derives from tyrosine nitrosylation or nitrosylation of the active-site cysteine (27).…”

Section: Discussionmentioning

confidence: 99%

Redox Regulation of Transglutaminase 2 Activity

Stamnæs

Pinkas

Fleckenstein

et al. 2010

Journal of Biological Chemistry

164

178

View full text Add to dashboard Cite

Transglutaminase 2 (TG2) in the extracellular matrix is largely inactive but is transiently activated upon certain types of inflammation and cell injury. The enzymatic activity of extracellular TG2 thus appears to be tightly regulated. As TG2 is known to be sensitive to changes in the redox environment, inactivation through oxidation presents a plausible mechanism. Using mass spectrometry, we have identified a redox-sensitive cysteine triad consisting of Cys 230 Human transglutaminase 2 (TG2) 2 modifies protein-or peptide-bound glutamine residues by either cross-linking their reactive carboxamide side chains to primary amines or by deamidation, converting glutamine residues to glutamate (1, 2). Ca 2ϩ is required for this catalytic activity and induces conformational changes in the enzyme, which arrange the active-site residues for catalysis, including Cys 277 (3-6). As TG2 is abundantly expressed in both the intracellular and extracellular environments of many tissues, its catalytic activity must be tightly regulated to avoid excess modification of cellular and tissue components. GTP and GDP act as allosteric inhibitors by inducing a closed conformation in which the active site is buried (6 -8). Low Ca 2ϩ concentration and high GTP/GDP concentration in the cytosol typically prevent TG2 activation within cells. Despite conditions in the extracellular milieu that favor activation, extracellular TG2 also appears to be predominantly inactive under normal conditions but can be activated by certain types of inflammation and cell injury (9).The catalytic activity of TG2 is implicated in the pathogenesis of several human diseases, including celiac disease (10). Celiac disease is caused by an aberrant immune response to proline-and glutamine-rich peptides from dietary gluten in the small intestine of genetically predisposed individuals (11). In the celiac immune response, the enzymatic activity of TG2 is crucial, as TG2-mediated deamidation of gluten peptides increases their T-cell antigenicity (12, 13).In contrast to our knowledge of the mechanistic basis for TG2 inactivity in the intracellular environment, the mechanisms underlying regulation of TG2 activity in the extracellular compartment remain unclear. TG2 harbors no disulfide bonds in its native state, which is unusual for enzymes in the extracellular environment (14). Previous studies have shown that TG2 is susceptible to oxidation, resulting in inactivation (19 -22). Thus, modulation of enzymatic activity through oxidation presents a plausible mechanism for regulation of extracellular TG2 activity. We have investigated the events underlying oxidative inactivation of TG2 and report the identification of a redox-sensitive cysteine triad consisting of Cys 230 , Cys 370 , and Cys 371 . Within this triad, Cys 230 appears to set the threshold for intramolecular disulfide bond formation and thereby inactivation. Oxidation was influenced by the presence of Ca 2ϩ and substrate, suggesting that the local environment can modulate and fine-tune oxidative inactivation of T...

show abstract

“…Asthma, induced by ovalbumin, involves the increased expression of TGF␤1 (49). TGaseII regulates the expression of TGF␤1 (50). Human mast cells show the increased expression of TGF␤1 in response to histamine (51).…”

Section: Discussionmentioning

confidence: 99%

Transglutaminase II/MicroRNA-218/-181a Loop Regulates Positive Feedback Relationship between Allergic Inflammation and Tumor Metastasis

Eom

Kim

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The mechanism of transglutaminase II-mediated allergic inflammation-promoted tumor metastasis remains unknown at the molecular level. Results: The transglutaminase II/miR-218/-181a loop regulates allergic inflammation-promoted tumor metastasis. Conclusion: Transglutaminase II mediates a positive feedback between allergic inflammation and tumor metastasis. Significance: Transglutaminase II can be a target for the development of allergy and cancer therapeutics.

show abstract

Increased TG2 Expression Can Result in Induction of Transforming Growth Factor β1, Causing Increased Synthesis and Deposition of Matrix Proteins, Which Can Be Regulated by Nitric Oxide

Cited by 66 publications

References 56 publications

The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26

The role of tissue transglutaminase (TG2) in regulating the tumour progression of the mouse colon carcinoma CT26

Redox Regulation of Transglutaminase 2 Activity

Transglutaminase II/MicroRNA-218/-181a Loop Regulates Positive Feedback Relationship between Allergic Inflammation and Tumor Metastasis

Contact Info

Product

Resources

About