Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer
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摘要
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
引文
1. Eyers PA, Keeshan K, Kannan N. Tribbles in the 21st century:the evolving roles of tribbles pseudokinases in biology and disease. Trends Cell Biol 2017;27:284–98.
2 . Murphy JM, Mace PD, Eyers PA. Live and let die:insights into pseudoenzyme mechanisms from structure. Curr Opin Struct Biol2017;47:95–104.
3 . Sakai S, Miyajima C, Uchida C, Itoh Y, Hayashi H, Inoue Y. Tribblesrelated protein family members as regulators or substrates of the ubiquitin-proteasome system in cancer development. Curr Cancer Drug Targets 2016;16:147–56.
4 . Stein SJ, Mack EA, Rome KS, Pear WS. Tribbles in normal and malignant haematopoiesis. Biochem Soc Trans 2015;43:1112–5.
5 . Johnston J, Basatvat S, Ilyas Z, Francis S, Kiss-Toth E. Tribbles in inflammation. Biochem Soc Trans 2015;43:1069–74.
6 . Liang KL, Rishi L, Keeshan K. Tribbles in acute leukemia. Blood2013;121:4265–70.
7 . Li K, Wang F, Cao WB, Lv XX, Hua F, Cui B, et al. TRIB3 Promotes APL progression through stabilization of the oncoprotein PML-RARαand inhibition of p53-mediated senescence. Cancer Cell 2017;31:697-710 .e7.
8 . Byrne DP, Foulkes DM, Eyers PA. Pseudokinases:update on their functions and evaluation as new drug targets. Future Med Chem2017;9:245–65.
9 . Carmody R, Keeshan K. The Tribble with APL:a new road to therapy.Cancer Cell 2017;31:612–3.
10 . Torrano V, Valcarcel-Jimenez L, Cortazar AR, Liu X, Urosevic J,Castillo-Martin M, et al. The metabolic co-regulator PGC1αsuppresses prostate cancer metastasis. Nat Cell Biol2016;18:645–56.
11. Arruabarrena-Aristorena A, Zabala-Letona A, Carracedo A. Oil for the cancer engine:the cross-talk between oncogenic signaling and polyamine metabolism. Sci Adv 2018;4:eaar2606.
12 . Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N,Fernandez-Ruiz S, Sutherland JD, Clasquin M, et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 2017;547:109–13.
13 . Valcarcel-Jimenez L, Gaude E, Torrano V, Frezza C, Carracedo A.Mitochondrial metabolism:yin and yang for tumor progression.Trends Endocrinol Metab 2017;28:748–57.
14 . Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis.Science 2011;331:1559–64.
15 . Teo Z, Sng MK, Chan JS, Lim MM, Li Y, Li L, et al. Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelialmesenchymal transition by inducing 14-3-3γexpression. Oncogene2017;36:6408–19.
16 . Zhu P, Goh YY, Chin HF, Kersten S, Tan NS. Angiopoietin-like 4:a decade of research. Biosci Rep 2012;32:211–9.
17 . Lichtenstein L, Mattijssen F, de Wit NJ, Georgiadi A, Hooiveld GJ,van der Meer R, et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab2010;12:580–92.
18 . Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, et al.Angiopoietin-like 4 protein elevates the prosurvival intracellular O2à:H2O2ratio and confers anoikis resistance to tumors. Cancer Cell2011;19:401–15.
19 . Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC, et al.Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A 2007;104:15448–53.
20 . Baron D, Ramstein G, Chesneau M, Echasseriau Y, Pallier A, Paul C,et al. A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft.Kidney Int 2015;87:984–95.
21 . Danger R, Chesneau M, Paul C, Guérif P, Durand M, Newell KA,et al. A composite score associated with spontaneous operational tolerance in kidney transplant recipients. Kidney Int2017;91:1473–81.
22 . Ashton-Chess J, Giral M, Mengel M, Renaudin K, Foucher Y,Gwinner W, et al. Tribbles-1 as a novel biomarker of chronic antibody-mediated rejection. J Am Soc Nephrol 2008;19:1116–27.
23 . Dugast E, Kiss-Toth E, Docherty L, Danger R, Chesneau M, Pichard V, et al. Identification of tribbles-1 as a novel binding partner of Foxp3in regulatory T cells. J Biol Chem 2013;288:10051–60.
24 . Steinl DC, Kaufmann BA. Ultrasound imaging for risk assessment in atherosclerosis. Int J Mol Sci 2015;16:9749–69.
25 . Burkhardt R, Toh SA, Lagor WR, Birkeland A, Levin M, Li X, et al.Trib1 is a lipid-and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest 2010;120:4410–4.
26 . Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, et al. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 2013;495:524–8.
27 . Bauer RC, Sasaki M, Cohen DM, Cui J, Smith MA, Yenilmez BO,et al. Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα. J Clin Invest 2015;125:3809–18.
28 . Du K, Herzig S, Kulkarni RN, Montminy M. TRB3:a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science2003;300:1574–7.
29 . Prudente S, Sesti G, Pandolfi A, Andreozzi F, Consoli A, Trischitta V.The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases. Endocr Rev 2012;33:526–46.
30 . Kathiresan S, Srivastava D. Genetics of human cardiovascular disease.Cell 2012;148:1242–57.
31 . Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S,Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013;45:1274–83.
32. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707–13.
33 . Wang G, Franklin R, Hong Y, Erusalimsky JD. Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol 2005;146:324–32.
34 . Hong Y, Wang G, del Arroyo AG, Hernandez J, Skene C, Erusalimsky JD. Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation:selectivity of anagrelide for the megakaryocytic lineage.Leukemia 2006;20:1117–22.
35 . Ahluwalia M, Donovan H, Singh N, Butcher L, Erusalimsky JD.Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction. J Thromb Haemost 2010;8:2252–61.
36 . Ahluwalia M, Butcher L, Donovan H, Killick‐Cole C, Jones PM,Erusalimsky JD. The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis. J Thromb Haemost 2015;13:1103–12.
37 . Butcher L, Ahluwalia M,?rd T, Johnston J, Morris RH, Kiss-Toth E,et al. Evidence for a role of TRIB3 in the regulation of megakaryocytopoiesis. Sci Rep 2017;7:6684.
38 . Murphy JM, Nakatani Y, Jamieson SA, Dai W, Lucet IS, Mace PD.Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase. Structure 2015;23:2111–21.
39 . Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, et al. Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. Sci Signal 2018;11:eaau0597.
40 . O'Connor C, Yalla K, SaloméM, Moka HA, Casta?eda EG, Eyers PA,et al. Trib2 expression in granulocyte–monocyte progenitors drives a highly drug resistant acute myeloid leukaemia linked to elevated Bcl2.Oncotarget 2018;9:14977–92.
41 . Liang KL, Paredes R, Carmody R, Eyers RA, Meyer S, McCarthy TV,et al. Human TRIB2 oscillates during the cell cycle and promotes ubiquitination and degradation of CDC25C. Int J Mol Sci2016;17:1378.
42 . Rheault TR, Caferro TR, Dickerson SH, Donaldson KH, Gaul MD,Goetz AS, et al. Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors. Bioorg Med Chem Lett 2009;19:817–20.
43 . Foulkes DM, Byrne DP, Yeung W, Shrestha S, Bailey FP, Ferries S,et al. Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2(TRIB2)pseudokinase in cancer cells. Sci Signal 2018;11:eaat7951.
44 . Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing:progress, challenges and recommendations. Nat Rev Drug Discov 2018 Available from:?https://doi.org/10.1038/nrd.2018.168?.
45 . Sung HY, Francis SE, Arnold ND, Holland K, Ernst V, Angyal A,et al. Enhanced macrophage tribbles-1 expression in murine experimental atherosclerosis. Biology 2012;1:43–57.
46 . Guan H, Shuaib A, De Leon DD, Angyal A, Salazar M, Velasco G,et al. Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways. Sci Rep 2016;6:32667.
47 . Gonzalez MW, Kann MG. Chapter 4:protein interactions and disease.PLoS Comput Biol 2012;8:e1002819.
48 . Zhang XW, Mi S, Li Z, Zhou JC, Xie J, Hua F, et al. Antagonism of interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes. Oncotarget2017;8:9922–34.
49 . Kim KW, Thakur N, Piggott CA, Omi S, Polanowska J, Jin Y, et al.Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development. BMC Biol 2016;14:104.
50. Das R, Sebo Z, Pence L, Dobens LL. Drosophila tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase. PLoS One 2014;9:e109530.
51 . Mata J, Curado S, Ephrussi A, R?rth P. Tribbles coordinates mitosis and morphogenesis in Drosophila by regulating string/CDC25 proteolysis. Cell 2000;101:511–22.
52 . Hill R, Madureira PA, Ferreira B, Baptista I, Machado S, Cola?o L, et al. TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT. Nat Commun2017;8:14687.
53 . SaloméM, Magee A, Yalla K, Chaudhury S, Sarrou E, Carmody RJ,et al. A Trib2-p38 axis controls myeloid leukaemia cell cycle and stress response signaling. Cell Death Dis 2018;9:443.
54 . Salazar M, Lorente M, García-Taboada E, Pérez Gómez E, Dávila D,Zú?iga-García P, et al. Loss of Tribbles pseudokinase-3 promotes Aktdriven tumorigenesis via FOXO inactivation. Cell Death Differ2015;22:131–44.
55 . Salazar M, Lorente M, García-Taboada E, Hernández-Tiedra S, Davila D, Francis SE, et al. The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochim Biophys Acta2013;1831:1573–8.
56 . Salazar M, Carracedo A, SalanuevaíJ, Hernández-Tiedra S, Egia A,Lorente M, et al. TRB3 links ER stress to autophagy in cannabinoid antitumoral action. Autophagy 2009;5:1048–9.
57 . Salazar M, Lorente M, García-Taboada E, Gómez EP, Dávila D,Zú?iga-García P, et al. TRIB3 suppresses tumorigenesis by controlling mTORC2/AKT/FOXO signaling. Mol Cell Oncol 2015;2:e980134.
58 . Salazar M, Lorente M, Orea-Soufi A, Dávila D, Erazo T, Lizcano J,et al. Oncosuppressive functions of tribbles pseudokinase 3. Biochem Soc Trans 2015;43:1122–6.
59 . Hua F, Shang S, Yang YW, Zhang HZ, Xu TL, Yu JJ, et al. TRIB3interacts withβ-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology 2018,Available from:?https://doi.org/10.1053/j.gastro.2018.10.031?.
60 . Yokoyama T, Kanno Y, Yamazaki Y, Takahara T, Miyata S,Nakamura T. Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis. Blood 2010;116:2768–75.
61 . Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T,et al. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood 2007;109:3998–4005.
62 . Yokoyama T, Nakatake M, Kuwata T, Couzinet A, Goitsuka R,Tsutsumi S, et al. MEIS1-mediated transactivation of synaptotagminlike 1 promotes CXCL12/CXCR4 signaling and leukemogenesis. J Clin Invest 2016;126:1664–78.
63 . Erazo T, Lorente M, López-Plana A, Mu?oz-Guardiola P, FernándezNogueira P, García-Martínez JA, et al. The new antitumor drug ABTL0812 inhibits the Akt/mTORC1 axis by upregulating tribbles-3pseudokinase. Clin Cancer Res 2016;22:2508–19.
64 . Hamdan N, Kritsiligkou P, Grant CM. ER stress causes widespread protein aggregation and prion formation. J Cell Biol 2017;216:2295–304.
65 . Hua F, Li K, Yu JJ, Lv XX, Yan J, Zhang XW, et al. TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations. Nat Commun 2015;6:7951.
66 . Cui B, Cao X, Zou W, Wan Y, Wang N, Wang Y, et al. Regulation of immune-related diseases by multiple factors of chromatin, exosomes,microparticles, vaccines, oxidative stress, dormancy, protein quality control, inflammation and microenvironment:a meeting report of 2017International Workshop of the Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine on Tumor Immunology.Acta Pharm Sin B 2017;7:532–40.
2 . Murphy JM, Mace PD, Eyers PA. Live and let die:insights into pseudoenzyme mechanisms from structure. Curr Opin Struct Biol2017;47:95–104.
3 . Sakai S, Miyajima C, Uchida C, Itoh Y, Hayashi H, Inoue Y. Tribblesrelated protein family members as regulators or substrates of the ubiquitin-proteasome system in cancer development. Curr Cancer Drug Targets 2016;16:147–56.
4 . Stein SJ, Mack EA, Rome KS, Pear WS. Tribbles in normal and malignant haematopoiesis. Biochem Soc Trans 2015;43:1112–5.
5 . Johnston J, Basatvat S, Ilyas Z, Francis S, Kiss-Toth E. Tribbles in inflammation. Biochem Soc Trans 2015;43:1069–74.
6 . Liang KL, Rishi L, Keeshan K. Tribbles in acute leukemia. Blood2013;121:4265–70.
7 . Li K, Wang F, Cao WB, Lv XX, Hua F, Cui B, et al. TRIB3 Promotes APL progression through stabilization of the oncoprotein PML-RARαand inhibition of p53-mediated senescence. Cancer Cell 2017;31:697-710 .e7.
8 . Byrne DP, Foulkes DM, Eyers PA. Pseudokinases:update on their functions and evaluation as new drug targets. Future Med Chem2017;9:245–65.
9 . Carmody R, Keeshan K. The Tribble with APL:a new road to therapy.Cancer Cell 2017;31:612–3.
10 . Torrano V, Valcarcel-Jimenez L, Cortazar AR, Liu X, Urosevic J,Castillo-Martin M, et al. The metabolic co-regulator PGC1αsuppresses prostate cancer metastasis. Nat Cell Biol2016;18:645–56.
11. Arruabarrena-Aristorena A, Zabala-Letona A, Carracedo A. Oil for the cancer engine:the cross-talk between oncogenic signaling and polyamine metabolism. Sci Adv 2018;4:eaar2606.
12 . Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N,Fernandez-Ruiz S, Sutherland JD, Clasquin M, et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 2017;547:109–13.
13 . Valcarcel-Jimenez L, Gaude E, Torrano V, Frezza C, Carracedo A.Mitochondrial metabolism:yin and yang for tumor progression.Trends Endocrinol Metab 2017;28:748–57.
14 . Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis.Science 2011;331:1559–64.
15 . Teo Z, Sng MK, Chan JS, Lim MM, Li Y, Li L, et al. Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelialmesenchymal transition by inducing 14-3-3γexpression. Oncogene2017;36:6408–19.
16 . Zhu P, Goh YY, Chin HF, Kersten S, Tan NS. Angiopoietin-like 4:a decade of research. Biosci Rep 2012;32:211–9.
17 . Lichtenstein L, Mattijssen F, de Wit NJ, Georgiadi A, Hooiveld GJ,van der Meer R, et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab2010;12:580–92.
18 . Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, et al.Angiopoietin-like 4 protein elevates the prosurvival intracellular O2à:H2O2ratio and confers anoikis resistance to tumors. Cancer Cell2011;19:401–15.
19 . Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC, et al.Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A 2007;104:15448–53.
20 . Baron D, Ramstein G, Chesneau M, Echasseriau Y, Pallier A, Paul C,et al. A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft.Kidney Int 2015;87:984–95.
21 . Danger R, Chesneau M, Paul C, Guérif P, Durand M, Newell KA,et al. A composite score associated with spontaneous operational tolerance in kidney transplant recipients. Kidney Int2017;91:1473–81.
22 . Ashton-Chess J, Giral M, Mengel M, Renaudin K, Foucher Y,Gwinner W, et al. Tribbles-1 as a novel biomarker of chronic antibody-mediated rejection. J Am Soc Nephrol 2008;19:1116–27.
23 . Dugast E, Kiss-Toth E, Docherty L, Danger R, Chesneau M, Pichard V, et al. Identification of tribbles-1 as a novel binding partner of Foxp3in regulatory T cells. J Biol Chem 2013;288:10051–60.
24 . Steinl DC, Kaufmann BA. Ultrasound imaging for risk assessment in atherosclerosis. Int J Mol Sci 2015;16:9749–69.
25 . Burkhardt R, Toh SA, Lagor WR, Birkeland A, Levin M, Li X, et al.Trib1 is a lipid-and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest 2010;120:4410–4.
26 . Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, et al. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 2013;495:524–8.
27 . Bauer RC, Sasaki M, Cohen DM, Cui J, Smith MA, Yenilmez BO,et al. Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα. J Clin Invest 2015;125:3809–18.
28 . Du K, Herzig S, Kulkarni RN, Montminy M. TRB3:a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science2003;300:1574–7.
29 . Prudente S, Sesti G, Pandolfi A, Andreozzi F, Consoli A, Trischitta V.The mammalian tribbles homolog TRIB3, glucose homeostasis, and cardiovascular diseases. Endocr Rev 2012;33:526–46.
30 . Kathiresan S, Srivastava D. Genetics of human cardiovascular disease.Cell 2012;148:1242–57.
31 . Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S,Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013;45:1274–83.
32. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707–13.
33 . Wang G, Franklin R, Hong Y, Erusalimsky JD. Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol 2005;146:324–32.
34 . Hong Y, Wang G, del Arroyo AG, Hernandez J, Skene C, Erusalimsky JD. Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation:selectivity of anagrelide for the megakaryocytic lineage.Leukemia 2006;20:1117–22.
35 . Ahluwalia M, Donovan H, Singh N, Butcher L, Erusalimsky JD.Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction. J Thromb Haemost 2010;8:2252–61.
36 . Ahluwalia M, Butcher L, Donovan H, Killick‐Cole C, Jones PM,Erusalimsky JD. The gene expression signature of anagrelide provides an insight into its mechanism of action and uncovers new regulators of megakaryopoiesis. J Thromb Haemost 2015;13:1103–12.
37 . Butcher L, Ahluwalia M,?rd T, Johnston J, Morris RH, Kiss-Toth E,et al. Evidence for a role of TRIB3 in the regulation of megakaryocytopoiesis. Sci Rep 2017;7:6684.
38 . Murphy JM, Nakatani Y, Jamieson SA, Dai W, Lucet IS, Mace PD.Molecular mechanism of CCAAT-enhancer binding protein recruitment by the TRIB1 pseudokinase. Structure 2015;23:2111–21.
39 . Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, et al. Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. Sci Signal 2018;11:eaau0597.
40 . O'Connor C, Yalla K, SaloméM, Moka HA, Casta?eda EG, Eyers PA,et al. Trib2 expression in granulocyte–monocyte progenitors drives a highly drug resistant acute myeloid leukaemia linked to elevated Bcl2.Oncotarget 2018;9:14977–92.
41 . Liang KL, Paredes R, Carmody R, Eyers RA, Meyer S, McCarthy TV,et al. Human TRIB2 oscillates during the cell cycle and promotes ubiquitination and degradation of CDC25C. Int J Mol Sci2016;17:1378.
42 . Rheault TR, Caferro TR, Dickerson SH, Donaldson KH, Gaul MD,Goetz AS, et al. Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors. Bioorg Med Chem Lett 2009;19:817–20.
43 . Foulkes DM, Byrne DP, Yeung W, Shrestha S, Bailey FP, Ferries S,et al. Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2(TRIB2)pseudokinase in cancer cells. Sci Signal 2018;11:eaat7951.
44 . Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing:progress, challenges and recommendations. Nat Rev Drug Discov 2018 Available from:?https://doi.org/10.1038/nrd.2018.168?.
45 . Sung HY, Francis SE, Arnold ND, Holland K, Ernst V, Angyal A,et al. Enhanced macrophage tribbles-1 expression in murine experimental atherosclerosis. Biology 2012;1:43–57.
46 . Guan H, Shuaib A, De Leon DD, Angyal A, Salazar M, Velasco G,et al. Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways. Sci Rep 2016;6:32667.
47 . Gonzalez MW, Kann MG. Chapter 4:protein interactions and disease.PLoS Comput Biol 2012;8:e1002819.
48 . Zhang XW, Mi S, Li Z, Zhou JC, Xie J, Hua F, et al. Antagonism of interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes. Oncotarget2017;8:9922–34.
49 . Kim KW, Thakur N, Piggott CA, Omi S, Polanowska J, Jin Y, et al.Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development. BMC Biol 2016;14:104.
50. Das R, Sebo Z, Pence L, Dobens LL. Drosophila tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase. PLoS One 2014;9:e109530.
51 . Mata J, Curado S, Ephrussi A, R?rth P. Tribbles coordinates mitosis and morphogenesis in Drosophila by regulating string/CDC25 proteolysis. Cell 2000;101:511–22.
52 . Hill R, Madureira PA, Ferreira B, Baptista I, Machado S, Cola?o L, et al. TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT. Nat Commun2017;8:14687.
53 . SaloméM, Magee A, Yalla K, Chaudhury S, Sarrou E, Carmody RJ,et al. A Trib2-p38 axis controls myeloid leukaemia cell cycle and stress response signaling. Cell Death Dis 2018;9:443.
54 . Salazar M, Lorente M, García-Taboada E, Pérez Gómez E, Dávila D,Zú?iga-García P, et al. Loss of Tribbles pseudokinase-3 promotes Aktdriven tumorigenesis via FOXO inactivation. Cell Death Differ2015;22:131–44.
55 . Salazar M, Lorente M, García-Taboada E, Hernández-Tiedra S, Davila D, Francis SE, et al. The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochim Biophys Acta2013;1831:1573–8.
56 . Salazar M, Carracedo A, SalanuevaíJ, Hernández-Tiedra S, Egia A,Lorente M, et al. TRB3 links ER stress to autophagy in cannabinoid antitumoral action. Autophagy 2009;5:1048–9.
57 . Salazar M, Lorente M, García-Taboada E, Gómez EP, Dávila D,Zú?iga-García P, et al. TRIB3 suppresses tumorigenesis by controlling mTORC2/AKT/FOXO signaling. Mol Cell Oncol 2015;2:e980134.
58 . Salazar M, Lorente M, Orea-Soufi A, Dávila D, Erazo T, Lizcano J,et al. Oncosuppressive functions of tribbles pseudokinase 3. Biochem Soc Trans 2015;43:1122–6.
59 . Hua F, Shang S, Yang YW, Zhang HZ, Xu TL, Yu JJ, et al. TRIB3interacts withβ-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology 2018,Available from:?https://doi.org/10.1053/j.gastro.2018.10.031?.
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