TRB2, a Mouse Tribbles Ortholog, Suppresses Adipocyte Differentiation by Inhibiting AKT and C/EBPβ

Naiki, Takahiro; Saijou, Eiko; Miyaoka, Yuichiro; Sekine, Keisuke; Miyajima, Atsushi

doi:10.1074/jbc.m701409200

Cited by 84 publications

(83 citation statements)

References 38 publications

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“…A mechanism for this was defined: Trbl binds to and promotes proteosome degradation of the fly C/EBP (CAAT enhancer binding protein) homolog encoded by the gene slow border cells (slbo), a key promoter of border cell migration. Subsequent work indicates that this interaction is highly conserved with Trib1 and Trib 2 in several mammalian tissues: (1) in acute myelogenous leukemia (AML) tumors, Trib1 accelerates degradation of C/EBPa; (2) upregulation of C/EBPb occurs in Trib1 knockout mice (Yamamoto et al, 2007;Keeshan et al, 2008); (3) overexpression of Trib2 reduces C/EBPa levels in a proteasome-dependent manner, resulting in myeloid differentiation (Keeshan et al, 2006); and (3) Trib2 (but not Trib3) increases degradation of C/EBPb, effectively suppressing differentiation of 3T3-L1 preadipocytes (Naiki et al, 2007).…”

Section: Developmental Dynamicsmentioning

confidence: 99%

“…This down-regulation of Tribs is critical to fat cell formation as on the one hand, continuous expression of Trib3 or Trib2 effectively blocks proliferation and adipogenesis, while on the other, knockdown leads to premature MCE and differentiation (Bezy et al, 2007;Naiki et al, 2007). How Tribs regulate the cell cycle in preadipocytes is not clear, but this block to differentiation is exerted in several ways: (1) repression of the activity of key transcription factors including C/EBPb, C/ EBPa (Bezy et al, 2007) and PPARg2 (Takahashi et al, 2008), (2) inhibition of Akt phosphorylation of Foxo1, which must be inactivated to allow fat cell development to proceed, and (3) degradation of acetyl coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (Qi et al, 2006).…”

Section: Adipocyte Differentiation and Hematopoiesis: Clues To Trib Rmentioning

confidence: 99%

“…How Tribs regulate the cell cycle in preadipocytes is not clear, but this block to differentiation is exerted in several ways: (1) repression of the activity of key transcription factors including C/EBPb, C/ EBPa (Bezy et al, 2007) and PPARg2 (Takahashi et al, 2008), (2) inhibition of Akt phosphorylation of Foxo1, which must be inactivated to allow fat cell development to proceed, and (3) degradation of acetyl coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (Qi et al, 2006). In addition, Trib1 binds LAP, the activating isoform of C/ EBPb, indicating that each Trib isoform contributes to the control of adipogenesis (Naiki et al, 2007).…”

Section: Adipocyte Differentiation and Hematopoiesis: Clues To Trib Rmentioning

confidence: 99%

“…In the cytoplasm, Tribs direct the proteosomal degradation of key signaling proteins, including ACC1 (Qi et al, 2006), SMURF1, FoxO (Matsumoto et al, 2006) and C/ EBP Naiki et al, 2007;Selim et al, 2007;Dedhia et al, 2010;Keeshan et al, 2010;Grandinetti et al, 2011). Also in the cytoplasm, Tribs bind to inactivate LAP (Naiki et al, 2007), MKKs (Kiss-Toth et al, 2004;Wang et al, 2011), and Akt (Du et al, 2003).…”

Section: Subcellular Localization Of Tribsmentioning

confidence: 99%

“…In fasting or diabetic mice Trib3 levels were increased, while both Trib3 and Trib2 were sufficient to block insulin dependent phosphorylation of Akt when misexpressed (Du et al, 2003). In adipocytes, each isoform contributes to fat cell differentiation: (1) Trib1 and Trib2 degrade C/EBPb, whereas Trib3 blocks transactivation but does not degrade C/ EBPb (Bezy et al, 2007;Naiki et al, 2007); (2) Trib3 and not Trib1 or Trib2 degrades ACC and the Trib3 COP1 binding site uniquely can confer this property ; and (3) Trib3 and Trib2 inhibit Akt activation, but Trib2 less effectively (Naiki et al, 2007).…”

Section: Overlapping and Opposing Activities Of Trib Isoformsmentioning

confidence: 99%

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Developmental roles of tribbles protein family members

Dobens

Bouyain

2012

Developmental Dynamics

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The gene tribbles (trbl), identified 12 years ago in genetic screens for mutations that control both cell division and cell migration during embryonic Drosophila development, is the founding member of the Tribbles (Trib) family of kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. Trib proteins share three motifs: (1) a divergent kinase region (Trib domain) with undetermined catalytic activity, (2) a COP1 site used to direct key target proteins to the proteosome for degradation, and (3) a MEK1 site that binds and modulates MAPKK kinase activity. The notion that Tribs act as scaffolding proteins to balance signaling levels in multiple pathways retains an attractive simplicity, but given recent data showing that divergent kinases act by means of novel catalytic mechanisms, the enzymatic activity of Tribs remains untested. Here, we focus on the role of Tribs during development. Developmental analysis of Drosophila trbl phenotypes reveals tissue-specific, sometimes contradictory roles. In mammals, multiple Trib isoforms exhibit overlapping and tissue-specific functions. Recent data indicate the mechanism of Trib activity is conserved and requires the Trib domain. Finally, we discuss the connections between Tribs in disease and cancer that have implications for their normal roles during organogenesis.

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Section: Developmental Dynamicsmentioning

confidence: 99%

Section: Adipocyte Differentiation and Hematopoiesis: Clues To Trib Rmentioning

confidence: 99%

Section: Adipocyte Differentiation and Hematopoiesis: Clues To Trib Rmentioning

confidence: 99%

Section: Subcellular Localization Of Tribsmentioning

confidence: 99%

Section: Overlapping and Opposing Activities Of Trib Isoformsmentioning

confidence: 99%

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Developmental roles of tribbles protein family members

Dobens

Bouyain

2012

Developmental Dynamics

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α‐tocopheryl‐phosphate regulation of gene expression in preadipocytes and adipocytes

Lirangi¹,

Meydani²,

Zingg³

et al. 2012

BioFactors

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A correct function of adipocytes in connection with cellular fatty acid loading and release is a vital aspect of energy homeostasis; dysregulation of these reactions can result in obesity and type 2 diabetes mellitus. In addition, adipocytes have been proposed to play a major role in preventing lipotoxicity by removing excess fatty acids from the circulation and converting them into triglycerides and thus decreasing the exposure of other cells to their potentially harmful effects. We report here that the addition of α-tocopheryl phosphate (but not α-tocopherol) to NIH3T3-L1 preadipocytes transcriptionally activates a set of genes TRB3 (Tribbles Homolog 3), Sestrin-2 (SESN2), and Insulin-Induced Gene 1 (INSIG1)] potentially preventing fat accumulation in these cells. In contrast, in differentiated adipocytes, α-tocopheryl phosphate is responsible for the transcriptional inhibition of the same genes, possibly facilitating fat uptake and storage. In conclusion, it appears that in proliferating preadipocytes α-tocopheryl phosphate foils fat accumulation, whereas in adipocytes it enhances it. These processes may be relevant in the regulation of excess fat accumulation and in prevention of lipotoxicity.

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Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling

Shu

Rosenberg

Cao

et al. 2012

Inflammatory Bowel Diseases

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Background Toll-like receptors (TLRs) are expressed by a variety of cells, including intestinal epithelia. However, the full spectrum of regulators modulating innate responses via TLRs has not been delineated. Tribbles (Trib) have been identified as a highly conserved family of kinase-like proteins. We sought to clarify the role of Trib2 in the TLR signaling pathway. Materials and Methods Trib2 mRNA and protein levels were analyzed by quantitative PCR and Western blot, respectively. Immunohistochemical staining was used to determine the expression of Trib2 in human tissue. Involvement of Trib2 in NF-κB pathways was assessed in epithelial cells by NF-κB reporter assay. Proteins that interacted with Trib2 were identified by mass spectrometry and confirmed by immunoprecipitation. The domain essential for Trib2 function was mapped using truncated constructs. Results Trib2 expression is decreased in active inflamed tissue from patients with inflammatory bowel disease. Trib2 is expressed in human and mouse colonic epithelium as well as immune cells, and its expression in epithelium is inducible in a ligand-dependent manner by TLR5 ligand stimulation. Trib2 inhibits TLR5-mediated activation of NF-κB downstream of TRAF6. Trib2 selectively modulates MAPK pathways p38 and JNK but not p44/p42 (ERK1/2). NF-κB2 (p100) was identified as a Trib2 binding partner in regulating the TLR5 signaling pathway that leads to inhibition of NF-κB activity. Residues 158–177 in the Trib 2 kinase-like domain are required for Trib2 function. Conclusions These observations indicate that Trib2 is a novel regulator in the TLR5 signaling pathway and altered expression of Trib2 may play a role in IBD.

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TRB2, a Mouse Tribbles Ortholog, Suppresses Adipocyte Differentiation by Inhibiting AKT and C/EBPβ

Cited by 84 publications

References 38 publications

Developmental roles of tribbles protein family members

Developmental roles of tribbles protein family members

α‐tocopheryl‐phosphate regulation of gene expression in preadipocytes and adipocytes

Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling

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