Alternative titles; symbols
HGNC Approved Gene Symbol: TRIB3
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:380,760-397,559 (from NCBI)
To identify proteins that modulate AKT activity, Du et al. (2003) used a yeast 2-hybrid assay to screen for proteins from a preadipocyte cDNA library that interacted with an AKT1 (164730) construct lacking the N-terminal pleckstrin homology domain. They identified a 354-amino acid protein previously identified as a neuronal cell death-inducible putative protein kinase (NIPK) in the rat and designated in the GenBank database as TRB3 (GenBank AY247738). TRB3 and its related family members TRB1 (TRIB1; 609461) and TRB2 (TRIB2; 609462) show 45% sequence identity overall and bear strong resemblances to 'tribbles,' a Drosophila protein that inhibits mitosis early in development by binding to the CDC25 homolog 'string' and promoting its ubiquitination and proteasome-mediated degradation. Like tribbles, TRB family members have a truncated kinase domain that lacks an adenosine 5-prime-triphosphate binding site (GXGXXG) and contains a variant catalytic core motif (TRB3: amino acids 175 to 182; LRDLKLRR vs consensus: HRDLKPEN). Correspondingly, Tribbles and its mammalian counterparts lack detectable kinase activity by in vitro kinase assay.
Wu et al. (2003) cloned TRIB3, which they designated SINK, from a human B-cell cDNA library. The deduced 358-amino acid protein contains a kinase-like domain and shares significant homology with serine/threonine protein kinases. Northern blot analysis detected SINK mRNA in spleen, thymus, prostate, liver, and pancreas, but not in other tissues examined.
By searching databases for sequences similar to TRIB1, Kiss-Toth et al. (2004) identified TRIB3. Quantitative real-time PCR of several tissues detected highest TRIB3 expression in pancreas, peripheral blood leukocytes, and bone marrow.
Du et al. (2003) demonstrated that TRB3 functions as a negative modulator of AKT. TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to AKT and blocking activation of the kinase. Amounts of TRB3 RNA and protein were increased in livers of db/db (see LEPR, 601007) diabetic mice compared with those of wildtype mice. Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance. Du et al. (2003) concluded that by interfering with AKT activation, TRB3 contributes to insulin resistance in individuals with susceptibility to type 2 diabetes (125853).
Wu et al. (2003) found that overexpression of SINK in human embryonic kidney cells inhibited NFKB (see 164011)-dependent transcription induced by TNF (191160) stimulation or by its downstream signaling proteins, but it did not inhibit NFKB translocation to the nucleus or binding of NFKB to DNA. Coimmunoprecipitation and in vitro kinase assays indicated that SINK specifically interacted with the NFKB transactivator p65 (RELA; 164014) and inhibited p65 phosphorylation. Consistent with its role in inhibiting NFKB-dependent transcription, SINK also sensitized cells to apoptosis induced by TNF and TRAIL (TNFSF10; 603598). Wu et al. (2003) concluded that SINK is involved in a negative feedback control pathway of NFKB-induced gene expression.
Kiss-Toth et al. (2004) found that overexpression of TRIB3 in HeLa cells inhibited AP1 (165160) activity and blocked oncogenic Ras (190020)-driven AP1 activation. ERK (see 601795) activation was enhanced by TRIB3, but only at low TRIB3 doses. Coimmunoprecipitation and yeast 2-hybrid assays showed that MEK1 (MAP2K1; 176872) interacted with both TRIB1 and TRIB3, and MKK7 (MAP2K7; 603014) interacted specifically with TRIB3. Cotransfection of MKK7 enhanced the level of TRIB3, indicating that the TRIB-MAPKK interaction stabilized TRIB3.
During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating acetyl-coenzyme A carboxylase (ACC; see 200350), the rate-limiting enzyme in fatty acid synthesis. Qi et al. (2006) described a parallel pathway, in which the pseudokinase TRB3, whose abundance is increased during fasting, stimulates lipolysis by triggering the degradation of ACC in adipose tissue. TRB3 promoted ACC ubiquitination through an association with the E3 ubiquitin ligase constitutive photomorphogenic protein-1 (COP1; 608067). Indeed, Qi et al. (2006) found that adipocytes deficient in TRB3 accumulated larger amounts of ACC protein than did wildtype cells. Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, Qi et al. (2006) concluded that their results demonstrated how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis.
Using purified Helicobacter pylori lipopolysaccharide (LPS) and TLR2 (603028)-positive and -negative stomach cancer cell lines, Smith et al. (2011) showed that H. pylori LPS induced NF-kappa-B (see 164011) activation and IL8 (146930) production via TLR2 and multiple downstream signaling components. H. pylori LPS also significantly decreased TRIB3 expression, and knockdown of TRIB3 enhanced the TLR2-mediated activating properties of H. pylori LPS. TRIB3 expression was also decreased by H. pylori through an LPS-independent mechanism via reduced CHOP (DDIT3; 126337) and ATF4 (604064) expression, resulting in NF-kappa-B activation and chemokine induction. Smith et al. (2011) concluded that TRIB3 modulation by H. pylori and/or its products may be an important mechanism of H. pylori-associated pathogenesis.
Stumpf (2024) mapped the TRIB3 gene to chromosome 20p13 based on an alignment of the TRIB3 sequence (GenBank AY247738) with the genomic sequence (GRCh38).
Du, K., Herzig, S., Kulkarni, R. N., Montminy, M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin by liver. Science 300: 1574-1577, 2003. [PubMed: 12791994] [Full Text: https://doi.org/10.1126/science.1079817]
Kiss-Toth, E., Bagstaff, S. M., Sung, H. Y., Jozsa, V., Dempsey, C., Caunt, J. C., Oxley, K. M., Wyllie, D. H., Polgar, T., Harte, M., O'Neill, L. A. J., Qwarnstrom, E. E., Dower, S. K. Human tribbles, a protein family controlling mitogen-activated protein kinase cascades. J. Biol. Chem. 279: 42703-42708, 2004. [PubMed: 15299019] [Full Text: https://doi.org/10.1074/jbc.M407732200]
Qi, L., Heredia, J. E., Altarejos, J. Y., Screaton, R., Goebel, N., Niessen, S., MacLeod, I. X., Liew, C. W., Kulkarni, R. N., Bain, J., Newgard, C., Nelson, M., Evans, R. M., Yates, J., Montminy, M. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. Science 312: 1763-1766, 2006. [PubMed: 16794074] [Full Text: https://doi.org/10.1126/science.1123374]
Smith, S. M., Moran, A. P., Duggan, S. P., Ahmed, S. E., Mohamed, A. S., Windle, H. J., O'Neill, L. A., Kelleher, D. P. Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide. J. Immun. 186: 2462-2471, 2011. [PubMed: 21220698] [Full Text: https://doi.org/10.4049/jimmunol.1000864]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/14/2024.
Wu, M., Xu, L.-G., Zhai, Z., Shu, H.-B. SINK is a p65-interacting negative regulator of NF-kappa-B-dependent transcription. J. Biol. Chem. 278: 27072-27079, 2003. [PubMed: 12736262] [Full Text: https://doi.org/10.1074/jbc.M209814200]