TRIB2

TRIB2
Identifiers
Aliases	TRIB2 , C5FW, GS3955, TRB2, tribbles pseudokinase 2
External IDs	OMIM: 609462; MGI: 2145021; HomoloGene: 41445; GeneCards: TRIB2; OMA:TRIB2 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2p24.3 Start 12,716,910 bp [1] End 12,742,734 bp [1]
Gene location (Mouse) Chr. Chromosome 12 (mouse) [2] Band 12|12 A1.1 Start 15,841,728 bp [2] End 15,866,923 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left ovary ganglionic eminence right ovary tibial nerve trigeminal ganglion spleen paraflocculus of cerebellum renal medulla left adrenal gland ventricular zone Top expressed in Gonadal ridge cumulus cell vas deferens efferent ductule medial ganglionic eminence interventricular septum atrioventricular valve saccule retina endocardial cushion More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding protein kinase activity protein kinase inhibitor activity transcription factor binding mitogen-activated protein kinase kinase binding ubiquitin protein ligase binding ubiquitin-protein transferase regulator activity Cellular component cytoplasm cytoskeleton nucleus Biological process regulation of MAP kinase activity protein phosphorylation negative regulation of fat cell differentiation positive regulation of proteasomal ubiquitin-dependent protein catabolic process negative regulation of protein kinase activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 28951 217410 Ensembl ENSG00000071575 ENSMUSG00000020601 UniProt Q92519 Q8K4K3 RefSeq (mRNA) NM_021643 NM_144551 RefSeq (protein) NP_067675 NP_653134 Location (UCSC) Chr 2: 12.72 – 12.74 Mb Chr 12: 15.84 – 15.87 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tribbles homolog 2 is an atypical protein kinase that is encoded in human by the TRIB2 gene. ^{[5] [6] [7] [8]} TRIB2 is a pseudokinase member of the (pseudoenzyme) class of signaling/scaffold proteins, possessing very low vestigial catalytic output in vitro and critical scaffolding signaling functions in cells. ^[9] It is known to signal to canonical MAPK and AKT pathways and to regulate the ubiquitination of substrates with important functions in cell proliferation that control the cell cycle. It has also been associated with various diseases, especially in human and murine blood and solid tumor models. ^[10] Like TRIB1 and TRIB3, TRIB2 has recently been considered as a potential allosteric drug target, ^[11] and its three dimensional structure has been solved with the aid of stabilizing nanobodies ^[12] corroborating the potential for new approaches for drug targeting outside the highly degraded ATP site ^[13] and is a putative regulator of cancer-associated signalling and survival through AKT pSer473 modulation. ^[14] Recent work has established a convincing link between targetable overexpression of TRIB2 and prostate cancer drug responses ^[15]

References

1. GRCh38: Ensembl release 89: ENSG00000071575 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020601 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Wu M, Xu LG, Zhai Z, Shu HB (Jul 2003). "SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription". J Biol Chem. 278 (29): 27072–9. doi: 10.1074/jbc.M209814200 . PMID   12736262.
6. Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS (Nov 2006). "Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia". Cancer Cell. 10 (5): 401–11. doi:10.1016/j.ccr.2006.09.012. PMC   2839500 . PMID   17097562.
7. Hegedus Z, Czibula A, Kiss-Toth E (Aug 2006). "Tribbles: novel regulators of cell function; evolutionary aspects". Cell Mol Life Sci. 63 (14): 1632–41. doi:10.1007/s00018-006-6007-9. PMC   11136108 . PMID   16715410. S2CID   24556931.
8. "Entrez Gene: TRIB2 tribbles homolog 2 (Drosophila)".
9. Bailey FP, et al. (2015). "The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylate very weakly in a metal-independent manner". Biochemical Society Transactions. 467 (1): 47–62. doi:10.1042/BJ20141441. PMC   4844368 . PMID   25583260.
10. Eyers PA, Keeshan K, Kannan N (2016). "Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease". Trends in Cell Biology. 27 (9): S0962-8924(16)30178-7. doi:10.1016/j.tcb.2016.11.002. PMC   5382568 . PMID   27908682.
11. Foulkes DM, Byrne DP, Eyers PA (2015). "Tribbles pseudokinases: novel targets for chemical biology and drug discovery?". Biochemical Society Transactions. 43 (5): 1095–1103. doi:10.1042/BST20150109. PMID   26517930.
12. Jamieson SA, Pudjihartono M, Horne CR, Viloria JS, Dunlop JL, McMillan HD, Day RC, Keeshan K, Murphy JM, Mace PD (2022). "Nanobodies identify an activated state of the TRIB2 pseudokinase". Structure. 30 (11): 1518–1529. doi:10.1016/j.str.2022.08.006. PMID   36108635.
13. Byrne DP, Foulkes DM, Eyers PA (2017). "Pseudokinases: update on their functions and evaluation as new drug targets". Future Medicinal Chemistry . 9 (2): 245–265. doi: 10.4155/fmc-2016-0207 . PMID   28097887.
14. Foulkes DM, Byrne DP, Yeun W, Shrestha S, Bailey FP, Ferries S, Eyers CE, Keeshan K, Wells C, Drewry DH, Zuercher WJ, Kannan N, Eyers PA (2018). "Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells". Science Signaling. 11: 14687. doi:10.1126/scisignal.aat7951. PMC   6553640 . PMID   30254057.
15. Monga J, Valeriote F, Hwang C, Gadgeel S, Ghosh J (2023). "Daclatasvir, an Antiviral Drug, Downregulates Tribbles 2 Pseudokinase and Resensitizes Enzalutamide-Resistant Prostate Cancer Cells". Molecular Cancer Therapeutics. 22: 381–392. doi:10.1158/1535-7163.mct-21-1002. PMID   36805730.

Further reading

• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• Kiss-Toth E, Bagstaff SM, Sung HY, et al. (2004). "Human tribbles, a protein family controlling mitogen-activated protein kinase cascades" (PDF). J. Biol. Chem. 279 (41): 42703–8. doi: 10.1074/jbc.M407732200 . PMID   15299019. S2CID   25829757.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC   528928 . PMID   15489334.
• Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. Bibcode:2005Natur.434..724H. doi: 10.1038/nature03466 . PMID   15815621.
• Zhang Y, Davis JL, Li W (2005). "Identification of tribbles homolog 2 as an autoantigen in autoimmune uveitis by phage display". Mol. Immunol. 42 (11): 1275–81. doi:10.1016/j.molimm.2004.11.020. PMID   15950723.
• Lim J, Hao T, Shaw C, et al. (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi: 10.1016/j.cell.2006.03.032 . PMID   16713569. S2CID   13709685.
• Lin KR, Lee SF, Hung CM, et al. (2007). "Survival factor withdrawal-induced apoptosis of TF-1 cells involves a TRB2-Mcl-1 axis-dependent pathway". J. Biol. Chem. 282 (30): 21962–72. doi: 10.1074/jbc.M701663200 . PMID   17545167.