Thioredoxin binding protein (TBP)-2/Txnip and α-arrestin proteins in cancer and diabetes mellitus

Abstract

Thioredoxin binding protein -2/ thioredoxin interacting protein is an α-arrestin protein that has attracted much attention as a multifunctional regulator. Thioredoxin binding protein -2 expression is downregulated in tumor cells and the level of thioredoxin binding protein is correlated with clinical stage of cancer. Mice with mutations or knockout of the thioredoxin binding protein -2 gene are much more susceptible to carcinogenesis than wild-type mice, indicating a role for thioredoxin binding protein -2 in cancer suppression. Studies have also revealed roles for thioredoxin binding protein -2 in metabolic control. Enhancement of thioredoxin binding protein -2 expression causes impairment of insulin sensitivity and glucose-induced insulin secretion, and β-cell apoptosis. These changes are important characteristics of type 2 diabetes mellitus. Thioredoxin binding protein -2 regulates transcription of metabolic regulating genes. Thioredoxin binding protein -2-like inducible membrane protein/ arrestin domain containing 3 regulates endocytosis of receptors such as the β(2)-adrenergic receptor. The α-arrestin family possesses PPXY motifs and may function as an adaptor/scaffold for NEDD family ubiquitin ligases. Elucidation of the molecular mechanisms of α-arrestin proteins would provide a new pharmacological basis for developing approaches against cancer and type 2 diabetes mellitus.

Keywords: cancer; diabetes mellitus; thioredoxin binding protein −2-like inducible membrane protein/ arrestin domain containing 3; thioredoxin binding protein −2/ thioredoxin interacting protein; α-arrestin.

Fig. 1

Transcriptional regulation of TBP-2. Gene expression of TBP-2 is enhanced by a wide variety of stimuli. For each stimulus, the specific binding sequence and transcription factor are indicated. HSE, heat shock element;⁽²⁹⁾ PPRE, peroxisome proliferator-activated receptor (PPAR) response element;⁽⁵⁰⁾ AP-1, activator protein-1; GKLF, gut-enriched Krüppel-like factor; MZF1, myeloid zinc finger 1, putative FOXO1a-binding site;⁽⁶⁶⁾ and ChoRE: carbohydrate response element.^(36,38) HSF1: heat shock factor 1; RXRα, retinoid X receptor α; KLF6, Krüppel-like factor 6;⁽⁴³⁾ NF-YA, nuclear transcription factor Y subunit α; ChREBP, carbohydrate response element-binding protein; Mlx, Max-like protein X.

Fig. 2

Aggravation of T2DM by TBP-2. In obesity, free fatty acids and hyperglycemia may augment expression of TBP-2. TBP-2 suppresses 1) insulin sensitivity by decreasing Akt phosphorylation and expression of insulin signal-regulating genes such as insulin receptor substrate-1 (IRS-1) gene in muscle; and 2) glucose-stimulated insulin secretion from pancreatic β-cells by enhancing expression of uncoupling protein (UCP)-2; augments 3) pancreatic β-cell apoptosis; and also causes 4) suppression of thioredoxin. These changes may together lead to aggravation of diabetic phenotypes.

Fig. 3

α-Arrestin family proteins. TBP-2/Txnip, ARRDC2, TLIMP/ARRDC3, and DRH1/ARRDC4 share high sequence homology. TBP-2 and ARRDC1, 2, 3, 4, and 5 all contain arrestin N and C domains. All but ARRDC5 possess conserved PPXY motifs.

Fig. 4

Regulation of G protein-coupled receptors by TLMP/ARRDC3. TLIMP/ARRDC3 is reported to interact and co-localize with the β₂-adrenergic receptor.⁽¹²⁵⁾ The β₂-adrenergic receptor is a pharmacologically important G protein-coupled receptor (GPCR) for regulation of dilation of bronchial smooth muscle cells and therapy for bronchial asthma. TLIMP/ARRDC3 may regulate endocytosis, signaling, ubiquitination, and degradation of the β₂-adrenergic receptor.

Fig. 5

Hypothetical model of the interaction between α-arrestin family proteins and NEDD family ubiquitin ligases. α-Arrestin proteins containing conserved PPXY motifs may interact with the WW domain of NEDD family ubiquitin ligases to regulate ubiquitination and degradation of substrate proteins.

Fig. 6

Hypothetical model of reciprocal regulation between thioredoxin and TBP-2. TBP-2 is maintained at low levels and may be degraded by NEDD family ubiquitin ligases such as ITCH. TBP-2 binds to importin α, moves to the nucleus, interacts with substrates, and may induce their degradation by the NEDD family. TBP-2 also acts as a negative regulator of thioredoxin (TRX). Interaction between thioredoxin and TBP-2 might regulate each other’s stability. TBP-2 might also transcriptionally regulate expression of thioredoxin.