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Gene Review

TRIB3  -  tribbles pseudokinase 3

Homo sapiens

Synonyms: C20orf97, NIPK, SINK, SKIP3, TRB-3, ...
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Disease relevance of TRIB3

  • We have identified SKIP3, a novel human kinase-like gene, which is overexpressed in multiple human tumors and is regulated by hypoxia [1].
  • We show that the normal tissue expression of SKIP3 is confined to human liver, while multiple primary human lung, colon, and breast tumors express high levels of SKIP3 transcript [1].
  • To test the functional role of TRB3 variants, either Q84 or R84 TRB3 full-length cDNAs were transfected in human HepG2 hepatoma cell lines [2].
  • Hepatic overexpression of TRB3 in amounts comparable to those in db/db mice promoted hyperglycemia and glucose intolerance [3].
  • TRB3 expression is remarkably reduced in prostate cancer PC-3 cells after inhibition of PI 3-kinase [4].

High impact information on TRIB3

  • These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress [5].
  • Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death [5].
  • Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction [5].
  • In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity [5].
  • MLKB1KO mice had increased insulin-stimulated Akt phosphorylation and a >80% decrease in muscle expression of TRB3, a recently identified Akt inhibitor [6].

Biological context of TRIB3

  • Endogenous SKIP3 protein accumulates within 48 h under hypoxic growth conditions in HT-29 and PC-3 cells, with upregulation of the SKIP3 mRNA transcript by 72 h [1].
  • These results indicate that SKIP3 may be an important participant in tumor cell growth [1].
  • The analysis of cDNA clones revealed the presence of several hNIPK mRNA isoforms, differing in their 5' regions upstream of the hNIPK translation initiation codon as a result of alternative transcription initiation and alternative splicing [7].
  • Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions [7].
  • These data provide the first evidence that TRB3 gene plays a role in human insulin resistance and related clinical outcomes [2].

Anatomical context of TRIB3

  • TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP [5].
  • In these studies we demonstrate that fibrates upregulate TRB3 expression in mitogen-activated lymphocytes [8].
  • Interestingly, TRB3 and CtIP co-localized to the nucleus in HeLa cells and exhibited a unique dot-like pattern [9].
  • PGC-1alpha or PGC-1beta overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1alpha overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling [10].
  • Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, these results demonstrate how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis [11].

Associations of TRIB3 with chemical compounds

  • ATF4, whose level is upregulated in the cells exposed to thapsigargin or arsenite, is able to bind to the 33-bp repeat and activate the hNIPK promoter [7].
  • Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation [5].
  • In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3 [12].
  • However, in the absence of glucose overexpression of TRB3 in PC-3 cells can interfere with apoptosis and restore growth on extracellular matrix [4].
  • Expression of NIPK was also induced in cultured sympathetic neurons by NGF deprivation and in cortical neurons exposed to the Ca2+ ionophore, A23187 [13].

Other interactions of TRIB3

  • We identified activating transcription factor 4 (ATF4) as a SKIP3-binding partner using the yeast-two-hybrid assay [1].
  • TRB3, a mammalian tribbles homolog, whose chromosomal region 20p13-p12 has been linked to human type 2 diabetes, impairs insulin signaling through the inhibition of Akt phosphorylation and is overexpressed in murine models of insulin resistance [2].
  • Fibrates activate a proximal TRB3 promoter construct and mutation or partial deletion of a potential PPAR response element does not alter the ability of fibrates to drive TRB3 expression [8].
  • Genotoxic stress (DNA damage)-inducing agents, by contrast, downregulate TRB3 expression and appear to do so through both p53-dependent and -independent mechanisms [14].
  • TRB3 has recently been identified as a potential pro-apoptotic protein that may modulate the Akt/PKB-dependent signaling pathway [14].


  1. SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia. Bowers, A.J., Scully, S., Boylan, J.F. Oncogene (2003) [Pubmed]
  2. The functional Q84R polymorphism of mammalian Tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from Italy. Prudente, S., Hribal, M.L., Flex, E., Turchi, F., Morini, E., De Cosmo, S., Bacci, S., Tassi, V., Cardellini, M., Lauro, R., Sesti, G., Dallapiccola, B., Trischitta, V. Diabetes (2005) [Pubmed]
  3. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Du, K., Herzig, S., Kulkarni, R.N., Montminy, M. Science (2003) [Pubmed]
  4. TRB3 is a PI 3-kinase dependent indicator for nutrient starvation. Schwarzer, R., Dames, S., Tondera, D., Klippel, A., Kaufmann, J. Cell. Signal. (2006) [Pubmed]
  5. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. Ohoka, N., Yoshii, S., Hattori, T., Onozaki, K., Hayashi, H. EMBO J. (2005) [Pubmed]
  6. Skeletal Muscle-Selective Knockout of LKB1 Increases Insulin Sensitivity, Improves Glucose Homeostasis, and Decreases TRB3. Koh, H.J., Arnolds, D.E., Fujii, N., Tran, T.T., Rogers, M.J., Jessen, N., Li, Y., Liew, C.W., Ho, R.C., Hirshman, M.F., Kulkarni, R.N., Kahn, C.R., Goodyear, L.J. Mol. Cell. Biol. (2006) [Pubmed]
  7. Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions. Ord, D., Ord, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  8. Fibrates upregulate TRB3 in lymphocytes independent of PPARalpha by augmenting CCAAT/enhancer-binding proteinbeta (C/EBPbeta) expression. Selim, E., Frkanec, J.T., Cunard, R. Mol. Immunol. (2007) [Pubmed]
  9. TRB3 interacts with CtIP and is overexpressed in certain cancers. Xu, J., Lv, S., Qin, Y., Shu, F., Xu, Y., Chen, J., Xu, B.E., Sun, X., Wu, J. Biochim. Biophys. Acta (2007) [Pubmed]
  10. PGC-1{alpha} and PGC-1beta have both similar and distinct effects on myofiber switching toward an oxidative phenotype. Mortensen, O.H., Frandsen, L., Schjerling, P., Nishimura, E., Grunnet, N. Am. J. Physiol. Endocrinol. Metab. (2006) [Pubmed]
  11. TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism. 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. Science (2006) [Pubmed]
  12. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzmán, M., Velasco, G., Iovanna, J.L. Cancer Res. (2006) [Pubmed]
  13. Identification of a novel kinase-like gene induced during neuronal cell death. Mayumi-Matsuda, K., Kojima, S., Suzuki, H., Sakata, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  14. Genotoxic and endoplasmic reticulum stresses differentially regulate TRB3 expression. Corcoran, C.A., Luo, X., He, Q., Jiang, C., Huang, Y., Sheikh, M.S. Cancer Biol. Ther. (2005) [Pubmed]
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