TRIB2 explained

Tribbles homolog 2 is an atypical protein kinase that is encoded in human by the TRIB2 gene.^{[1] [2] [3] [4]} 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.^[5] 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 ccyle. It has also been associated with various diseases, especially in human and murine blood and solid tumor models.^[6] Like TRIB1 and TRIB3, TRIB2 has recently been considered as a potential allosteric drug target,^[7] and its three dimensional structure has been solved with the aid of stabilizing nanobodies ^[8] corroborating the potential for new approaches for drug targeting outside the highly degraded ATP site ^[9] and is a putative regulator of cancer-associated signalling and survival through AKT pSer473 modulation.^[10] Recent work has established a convincing link between targetable overexpression of TRIB2 and prostate cancer drug responses ^[11]

Further reading

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

Notes and References

1. Wu M, Xu LG, Zhai Z, Shu HB . SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription . J Biol Chem . 278 . 29 . 27072–9 . Jul 2003 . 12736262 . 10.1074/jbc.M209814200 . free.
2. 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 . Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia . Cancer Cell . 10 . 5 . 401–11 . Nov 2006 . 17097562 . 2839500. 10.1016/j.ccr.2006.09.012 .
3. Hegedus Z, Czibula A, Kiss-Toth E . Tribbles: novel regulators of cell function; evolutionary aspects . Cell Mol Life Sci . 63 . 14 . 1632–41 . Aug 2006 . 16715410 . 10.1007/s00018-006-6007-9 . 24556931 . 11136108 .
4. Web site: Entrez Gene: TRIB2 tribbles homolog 2 (Drosophila).
5. Bailey FP, et al . The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylate very weakly in a metal-independent manner. . Biochemical Society Transactions . 467 . 1 . 47–62 . 2015 . 25583260 . 10.1042/BJ20141441. 4844368.
6. Eyers PA, Keeshan K, Kannan N . 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 . 2016 . 27908682 . 10.1016/j.tcb.2016.11.002. 5382568.
7. Foulkes DM, Byrne DP, Eyers PA . Tribbles pseudokinases: novel targets for chemical biology and drug discovery? . Biochemical Society Transactions . 43 . 5 . 1095–1103 . 2015 . 26517930 . 10.1042/BST20150109.
8. Jamieson SA, Pudjihartono M, Horne CR, Viloria JS, Dunlop JL, McMillan HD, Day RC, Keeshan K, Murphy JM, Mace PD . Nanobodies identify an activated state of the TRIB2 pseudokinase . Structure . 30 . 11 . 1518–1529 . 2022 . 36108635 . 10.1016/j.str.2022.08.006.
9. Byrne DP, Foulkes DM, Eyers PA . Pseudokinases: update on their functions and evaluation as new drug targets. . . 9 . 2 . 245–265. 2017 . 28097887. 10.4155/fmc-2016-0207. free .
10. 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 . Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells . Science Signaling . 11 . 14687 . 2018 . 28276427 . 10.1126/scisignal.aat795.
11. Monga J, Valeriote F, Hwang C, Gadgeel S, Ghosh J. Daclatasvir, an Antiviral Drug, Downregulates Tribbles 2 Pseudokinase and Resensitizes Enzalutamide-Resistant Prostate Cancer Cells . Molecular Cancer Therapeutics . 22 . 381–392 . 2023 . 28276427 . 10.1126/scisignal.aat795.