α1-Adrenergic Receptor Signaling via Gh Is Subtype Specific and Independent of Its Transglutaminase Activity

Chen, Songhai; Lin, Fang; Iismaa, Siiri E.; Lee, Kyung N.; Birckbichler, Paul J.; Graham, Robert M.

doi:10.1074/jbc.271.50.32385

Cited by 105 publications

(78 citation statements)

References 28 publications

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“…However, this latter function, unlike other functions described for TG2, was not calcium-dependent and was not inhibited by GTP. TG2 has also been reported to function as novel G protein-coupled membrane receptor (16) and has been shown to have a role in transmitting signals from classical seven-transmembrane helix G-coupled receptors such as the ␣ 1B -adrenergic receptor (17). Here we report that TG2 has another novel enzymatic function, namely kinase activity.…”

Section: Discussionmentioning

confidence: 64%

Tissue Transglutaminase Has Intrinsic Kinase Activity

Mishra

Murphy

2004

Journal of Biological Chemistry

173

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Tissue transglutaminase (TG2) is a ubiquitous enzyme that cross-links glutamine residues with lysine residues, resulting in protein polymerization, cross-linking of dissimilar proteins, and incorporation of diamines and polyamines into proteins. It has not previously been known to have kinase activity. Recently, insulin-like growth factor-binding protein-3 (IGFBP-3) has been reported to be phosphorylated by breast cancer cell membranes. We purified the IGFBP-3 kinase activity from solubilized T47D breast cancer cell membranes using gel filtration, ion-exchange chromatography, and IGFBP-3 affinity chromatography. The fractions containing kinase activity were further purified by high pressure liquid chromatography and analyzed by tandem mass spectroscopy. TG2 was detected in fractions containing kinase activity. Antisera to TG2 and protein A-Sepharose were used to immunoprecipitate TG2 from membrane fractions. The immunoprecipitates retained IG-FBP-3 kinase, whereas immunoprecipitation deleted kinase activity in the membrane supernatant. The inhibitors of TG2, cystamine and monodansyl cadaverine, abolished the ability of the T47D cell membrane preparation to phosphorylate IGFBP-3. Both TG2 purified from guinea pig liver and recombinant human TG2 expressed in insect cells were able to phosphorylate IGFBP-3. TG2 kinase activity was inhibited in a concentration-dependent fashion by calcium, which has previously been shown to be important for the cross-linking activity of TG2. These data provide compelling evidence that TG2 has intrinsic kinase activity, a function that has not previously been ascribed to TG2. Furthermore, we provide evidence that TG2 is a major component of the IGFBP-3 kinase activity present on breast cancer cell membranes.

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Section: Discussionmentioning

confidence: 64%

Tissue Transglutaminase Has Intrinsic Kinase Activity

Mishra

Murphy

2004

Journal of Biological Chemistry

173

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Section: Discussionmentioning

confidence: 99%

“…We have not formally excluded that the GTP-binding activity of p.M330R, p.I331N and p.N333S mutants might also be abnormal. However, we believe that this is unlikely, considering that two different domains of TG2 are responsible for these functions as demonstrated by the fact that the p.C277S dominant-negative mutant, which is devoid of transamidating activity, still retains its G-protein activity (Chen et al, 1996).In conclusion, TGM2 mutations in these patients seem to interact with other factor(s) (such as insulin resistance) to give rise to impairment of glucose metabolism. The identification of the substrate(s) of TG2 in the β cell will be instrumental in unravelling the physiological role of TG2 in insulin secretion.…”

mentioning

confidence: 86%

Missense mutations in theTGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes

et al. 2007

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Transglutaminase 2 (TG2 or TGM2) is a multi-functional enzyme which catalyzes transamidation reactions or acts as a G-protein in intracellular signalling. Tgm2 -/-Mice lacking TG2 activity are glucose intolerant and show impairment of insulin secretion, suggesting an important physiological role for TG2 in the pancreatic β cell. We have previously described a TGM2 heterozygous missense mutation ((c.998A>G, p.N333S) in a 14 year-old patient with insulin-treated diabetes and in his diabetic father. The aim of this study was to further investigate the role of TG2 in early-onset type 2 diabetes. We analysed the TGM2 gene in 205 patients with clinically defined Maturity Onset Diabetes of the Young (MODY) or early-onset type 2 diabetes. We found two novel heterozygous mutations (c.989T>G, p.M330R; c.992T>A, p.I331N), which were not detected in 300 normoglycemic controls. All mutations were in residues which are located close to the catalytic site and impaired transamidating activity in vitro. Gene expression of TGM family genes and localization of TG2 in normal human pancreas indicated that TG2 is the only transglutaminase significantly expressed in human pancreatic islet cells. We conclude that reduced TG2 activity can contribute to disorders of glucose metabolism possibly via an impairment of insulin secretion. © 2007 Wiley-Liss, Inc. INTRODUCTIONTransglutaminase 2 (TG2; EC 2.3.2.13) is an ubiquitous enzyme with two well established, reciprocally regulated, activities: it cross-links proteins by virtue of its transamidating activity and acts as a G-protein in intracellular signalling (Griffin et al., 2002;Lorand and Graham, 2003). TG2 has been involved in several cellular processes such as cell adhesion and cell death, but its physiological role is still a matter of debate (Griffin et al., 2002;Lorand and Graham, 2003). In order to shed light on the function of TG2 in mammals, TG2 knock-out mice (Tgm2 -/-) have been generated (Bernassola et al., 2002;Nanda et al., 2001). Surprisingly, mice lacking TG2 activity do not show any major defects in apoptosis, but rather are glucose intolerant and show impairment of insulin secretion, suggesting a physiological role for TG2 in the pancreatic β cell (Bernassola et al., 2002). This is in keeping with previous studies showing that agents known to inhibit transglutaminase activity (e.g. monodansylcadaverine) can decrease glucose-stimulated insulin secretion from rat pancreatic islets in a dose-related manner (Sener et al., 1985, Bungay et al., 1986. In addition, we have described a TG2 heterozygous missense mutation p.N333S (c.998A>G) located in the TG2 catalytic site in a family clinically classified as maturity onset diabetes of the young (MODY; MIM# 606391) (Fig. 1A) (Bernassola et al., 2002). Thus, the aim of this study was to further investigate whether additional mutations in TG2 were also associated with early-onset type 2 diabetes (MIM# 125853). SUBJECTS AND METHODS Families with maturity onset diabetes of the young (MODY) or early onset type 2 diabetesWe studied the ...

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“…In this capacity, TG2 is involved as a signal transducing protein, mediating the activation of the delta1 isoform phospholipase C by the alpha 1B -and alpha 1D -adrenergic receptors (132,133) thereby increasing inositol phosphate turnover in TG2-transfected cells. However, although mice overexpressing TG2 in the myocardium develop a phenotype of LVH, there was no evidence in this model for a direct link between TG2 and inositol phosphate hydrolysis (134).…”

Section: Transglutaminases and Signal Transductionmentioning

confidence: 99%

Roles of transglutaminases in cardiac and vascular diseases

Sane

Kontos²,

Greenberg³

2007

Front Biosci

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All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

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α1-Adrenergic Receptor Signaling via Gh Is Subtype Specific and Independent of Its Transglutaminase Activity

Cited by 105 publications

References 28 publications

Tissue Transglutaminase Has Intrinsic Kinase Activity

Tissue Transglutaminase Has Intrinsic Kinase Activity

Missense mutations in theTGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes

Roles of transglutaminases in cardiac and vascular diseases

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