Functional mapping of Toll/interleukin-1 signalling networks by expression cloning

Kiss-Tóth, Endre; Wyllie, David; Holland, Karen; Marsden, Luke; Jozsa, Veronika; Oxley, K. M.; Polgár, Tímea; Qwarnström, Eva E.; Dower, Steven K.

doi:10.1042/bst0331405

Cited by 9 publications

(4 citation statements)

References 9 publications

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“…TRIB3 proteins appear to act as activators and inhibitors of MAPK activity, depending on the ratio of TRIB3 to MAPKK in the cell. In mammalian cells, TRIB3 at a relatively low level can activate MAPK phosphorylation, especially ERK1/2 phosphorylation (25,26). Interestingly, overexpression of TRIB3 decreased insulin-stimulated ERK1/2 phosphorylation in muscle cells but increased ERK1/2 phosphorylation under basal conditions in our experiments.…”

Section: E571 Trib3 Impairs Insulin Action In Skeletal Musclementioning

confidence: 47%

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

Liu

Franklin

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. glucose toxicity; type 2 diabetes; insulin signaling THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) is rapidly increasing in Westernized nations. Although it likely results from both genetic and environment factors, a key pathogenic characteristic of T2DM is insulin resistance, due to impaired stimulation of glucose uptake in skeletal muscle.To obtain a more comprehensive understanding of insulin resistance, we have performed cDNA microarray studies to systematically assess differential gene expression in skeletal muscle from insulin-sensitive (IS) vs. insulin-resistant (IR) humans (59, 60). These analyses identified Tribbles homolog 3 (TRIB3) as a gene with increased expression in patients with T2DM. Tribbles was first identified by Mata et al. (31) in 2000 as a regulator of germ-cell development in Drosophila (31). Tribbles inhibits mitosis and regulates DNA damage repair by promoting ubiquitination and proteasome-mediated degradation of specific cell cycle regulators early in development (17,31,46,49). Mammals express a family of three genes, TRIB1, TRIB2, and TRIB3, that are homologous to Tribbles. These family members are characterized by a variant kinase domain in the center of molecule with a high homology to serine/ threonine kinases (22). However, they app...

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Section: E571 Trib3 Impairs Insulin Action In Skeletal Musclementioning

confidence: 47%

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

Liu

Franklin

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…However, the biological relevance of this interaction is still unknown as there has been no independent confirmation and further characterisation of trb-1/12-LOX binding. Our group have reported recently the identification of human tribbles-1 as a novel regulator of AP-1 activation in a screen [9], which is designed to rapidly annotate signalling network components based on their function [13][14][15]. Further characterisation of trb-1 function revealed that this protein (similarly to trb-3) binds to the 'middle layer' of kinases in the MAPK network, the MAPKKs [16].…”

Section: Mammalian Tribblesmentioning

confidence: 98%

Tribbles: novel regulators of cell function; evolutionary aspects

Hegedűs

Czibula

Kiss-Tóth

2006

Cell. Mol. Life Sci.

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Identification of rate-limiting steps or components of intracellular second messenger systems holds promise to effectively interfere with these pathways under pathological conditions. The emerging literature on a recently identified family of signalling regulator proteins, called tribbles gives interesting clues for how these proteins seem to link several 'independent' signal processing systems together. Via their unique way of action, tribbles co-ordinate the activation and suppression of the various interacting signalling pathways and therefore appear to be key in determining cell fate while responding to environmental challenges. This review summarises our current understanding of tribbles function and also provides an evolutionary perspective on the various tribbles genes.

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“…Using a genome-wide functional screen for components of inflammatory signalling networks, we identified a novel protein, human homologue of Drosophila tribbles (trb) [44,45] that is critically required for regulation of IL-8 expression in HeLa cells. A subsequent database search revealed the existence of three mammalian tribbles-like proteins (Htrb1, 2 and 3) and we have shown that these selectively regulate the activation of ERKs, JNKs and p38 MAPK by interacting with MAP kinase kinases (MAPKKs) in a specific manner that regulates their activity [46].…”

Section: Introductionmentioning

confidence: 99%

Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific

et al. 2006

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Functional mapping of Toll/interleukin-1 signalling networks by expression cloning

Cited by 9 publications

References 9 publications

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

Tribbles: novel regulators of cell function; evolutionary aspects

Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific

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