IKBKE-DRIVEN TPL2 AND MEK1 PHOSPHORYLATIONS SUSTAIN CONSTITUTIVE ERK1/2 ACTIVATION IN TUMOR CELLS

Cancer cells; ERK1/2 (MAPK1/2); IKKɛ (IKBKE); MEK1 (MAP2K1); Signal transduction; TPL2 (MAP3K8); Molecular Medicine; Animal Science and Zoology; Pharmacology; Drug Discovery

Abstract :

[en] IKBKE have been associated with numerous cancers. As a result, IKBKE have emerged as potential target for cancer therapy. Accumulating evidence support that IKBKE orchestrate tumor cell survival in cancers. Here we evaluated the possible link between IKBKE and ERK phosphorylation. The effects of IKBKE silencing on MAPK activation in tumor vs. normal cells were evaluated via WB and RT-PCR. Ectopically expressed IKBKE, TPL2 or MEK1 constructs were used to examine the possible interactions among them via co-IP. In vitro kinase assays were performed to understand nature of the observed interactions. In tumors, IKBKE regulates MEK/ERK constitutive activations in vitro and in vivo. IKBKE and TPL2 physically interact and this interaction leads to TPL2 phosphorylation. We describe here a novel regulatory link between IKBKE and constitutive ERK1/2 activation in tumor cells. This new circuitry may be relevant for tumor cell survival in various malignancies.

Disciplines :

Oncology
Biochemistry, biophysics & molecular biology

Author, co-author :

Göktuna, Serkan ; Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-Research

Language :

English

Title :

IKBKE-DRIVEN TPL2 AND MEK1 PHOSPHORYLATIONS SUSTAIN CONSTITUTIVE ERK1/2 ACTIVATION IN TUMOR CELLS

Publication date :

03 January 2022

Journal title :

EXCLI Journal

eISSN :

1611-2156

Publisher :

Leibniz Research Centre for Working Environment and Human Factors

Volume :

Pages :

436 - 453

Peer reviewed :

Peer Reviewed verified by ORBi

Funding text :

Studies reported here were supported by F.N.R.S, FLF and WELBIO funds in Belgium and TÜBİTAK ARDEB 116Z349 grant in Turkey.

Available on ORBi :

since 08 March 2022

Statistics

Number of views

60 (1 by ULiège)

Number of downloads

27 (1 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Beinke S, Robinson MJ, Hugunin M, Ley SC. Lipopolysaccharide activation of the TPL-2/MEK/extracellu-lar signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105. Mol Cell Biol. 2004;24:9658–67. doi:10.1128/MCB.24.21.9658-9667.2004.
Bermudez O, Pagès G, Gimond C. The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol. 2010;299:C189-202. doi:10.1152/ajpcell.00347.200.
Bulek K, Liu C, Swaidani S, Wang L, Page RC, Gulen MF, et al. The inducible ki-nase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflamma-tion. Nat Immunol. 2011;12:844–52. doi:10.1038/ni.208.
Channavajhala PL, Wu L, Cuozzo JW, Hall JP, Liu W, Lin L-L, et al. Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. J Biol Chem. 2003;278:47089–97. doi:10.1074/jbc.M306002200.
Chariot A, Leonardi A, Muller J, Bonif M, Brown K, Siebenlist U. Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO con-nects IKK complexes with IKK epsi-lon and TBK1 kinases. J Biol Chem. 2002;277:37029–36. doi:10.1074/jbc.M205069200.
Cho J, Tsichlis PN. Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide. Proc Natl Acad Sci U S A. 2005;102:2350–5. doi:10.1073/pnas.0409856102.
Dang A, Frost JA, Cobb MH. The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. J Biol Chem. 1998;273:19909–13. doi:10.1074/jbc.273.31.19909.
Deschênes-Simard X, Gaumont-Leclerc M-F, Bourdeau V, Lessard F, Moiseeva O, Forest V, et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev. 2013;27:900–15. doi:10.1101/gad.203984.112.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–90. doi:10.1038/sj.onc.1210421.
Dodhiawala PB, Khurana N, Zhang D, Cheng Y, Li L, Wei Q, et al. TPL2 en-forces RAS-induced inflammatory sig-naling and is activated by point muta-tions. J Clin Invest. 2020;130:4771–90. doi:10.1172/JCI137660.
Durand JK, Zhang Q, Baldwin AS. Roles for the IKK-related kinases TBK1 and IKKε in cancer. Cells. 2018;7(9):139. doi:10.3390/cells7090139.
Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22:3497–508. doi:10.1128/MCB.22.10.3497-3508.2002.
Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008;14:342–6. doi:10.1158/1078-0432.CCR-07-4790.
Gantke T, Sriskantharajah S, Ley SC. Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase. Cell Res. 2011;21(1):131–45. doi:10.1038/cr.2010.173.
Gianì F, Russo G, Pennisi M, Sciacca L, Frasca F, Pappalardo F. Computational modeling reveals MAP3K8 as mediator of resistance to vemurafenib in thyroid cancer stem cells. Bioinformatics. 2019;35:2267–75. doi:10.1093/bioinformatics/bty969.
Göktuna SI, Canli Ö, Bollrath J, Fingerle AA, Horst D, Diamanti M, et al. IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells. Cell Rep. 2014;7:1914-25. doi: 10.1016/j.celrep.2014.05.006.
Göktuna SI, Shostak K, Chau T-L, Heukamp LC, Hennuy B, Duong H-Q, et al. The prosurvival IKK-related kinase IKKε integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine. Cancer Res. 2016;76:2587–99. doi:10.1158/0008-5472.CAN-15-1473.
Göktuna Sİ. IKBKE inhibits TSC1 to activate the mTOR/S6K pathway for oncogenic transformation. Turk J Biol. 2018;42:268–78. doi:10.3906/biy-1801-57.
Goettel JA, Liang D, Hilliard VC, Edelblum KL, Broadus MR, Gould KL, et al. KSR1 is a functional protein kinase capable of serine autophosphorylation and direct phosphorylation of MEK1. Exp Cell Res. 2011;317:452–63. doi:10.1016/j.yexcr.2010.11.018.
Gruosso T, Garnier C, Abelanet S, Kieffer Y, Lemesre V, Bellanger D, et al. MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas. Nat Commun. 2015;68583. doi:10.1038/ncomms9583.
Guma M, Stepniak D, Shaked H, Spehlmann ME, Shenouda S, Cheroutre H, et al. Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation. J Exp Med. 2011;208:1889–900. doi:10.1084/jem.20110242.
Hanafusa H, Torii S, Yasunaga T, Nishida E. Sprouty1 and Sprouty2 provide a con-trol mechanism for the Ras/MAPK sig-nalling pathway. Nat Cell Biol. 2002;4:850–8. doi:10.1038/ncb867.
Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43(Database issue):D512-20. doi:10.1093/nar/gku1267.
House CD, Grajales V, Ozaki M, Jordan E, Wubneh H, Kimble DC, et al. IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts. BMC Cancer. 2018;18(1):595. doi:10.1186/s12885-018-4507-2.
Huang W, Alessandrini A, Crews CM, Erikson RL. Raf-1 forms a stable complex with Mek1 and activates Mek1 by serine phosphorylation. Proc Natl Acad Sci U S A. 1993;90:10947–51. doi:10.1073/pnas.90.23.10947.
Kim G, Khanal P, Lim S-C, Yun HJ, Ahn S-G, Ki SH, et al. Interleukin-17 induces AP-1 activity and cellular transfor-mation via upregulation of tumor pro-gression locus 2 activity. Carcinogenesis. 2013;34:341–50. doi:10.1093/carcin/bgs342.
Kortum RL, Johnson HJ, Costanzo DL, Volle DJ, Razidlo GL, Fusello AM, et al. The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12induced and replicative senescence. Mol Cell Biol. 2006;26:2202–14. doi:10.1128/MCB.26.6.2202-2214.2006.
Lavoie H, Sahmi M, Maisonneuve P, Marullo SA, Thevakumaran N, Jin T, et al. MEK drives BRAF activation through allosteric control of KSR proteins. Nature. 2018;554(7693):549–53. doi:10.1038/na-ture25478.
Lavoie H, Gagnon J, Therrien M. ERK signalling: a master regulator of cell behaviour, life and fate. Nat Rev Mol Cell Biol. 2020;21:607–32. doi:10.1038/s41580-020-0255-7.
Lee HW, Choi HY, Joo KM, Nam D-H. Tumor progression locus 2 (Tpl2) kinase as a novel therapeutic target for cancer: double-sided effects of Tpl2 on cancer. Int J Mol Sci. 2015;16:4471–91. doi:10.3390/ijms16034471.
Lee SH, Jhun J, Byun J-K, Kim E-K, Jung K, Lee JE, et al. IL-17 axis accelerates the inflammatory progression of obese in mice via TBK1 and IKBKE pathway. Immunol Lett. 2017;184:67–75. doi:10.1016/j.im-let.2017.02.004.
Lehmann BD, Shaver TM, Johnson DB, Li Z, Gonzalez-Ericsson PI, Sánchez V, et al. Identification of targetable recurrent MAP3K8 rearrangements in melanomas lacking known driver mutations. Mol Cancer Res. 2019;17:1842–53. doi:10.1158/1541-7786.MCR-19-0257.
Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34. doi:10.1016/j.cell.2010.06.011.
Lin AW, Lowe SW. Oncogenic Ras activates the ARFp53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci U S A. 2001;98:5025–30. doi:10.1073/pnas.091100298.
Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12:3008–19. doi:10.1101/gad.12.19.3008.
Liu Y, Lagowski J, Sundholm A, Sundberg A, KuleszMartin M. Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4. Cancer Res. 2007;67:10711–9. doi:10.1158/0008-5472.CAN-07-1968.
Lozano J, Xing R, Cai Z, Jensen HL, Trempus C, Mark W, et al. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res. 2003;63:4232–8.
Martel G, Bérubé J, Rousseau S. The protein kinase TPL2 is essential for ERK1/ERK2 activation and cytokine gene expression in airway epithelial cells exposed to pathogen-associated molecular patterns (PAMPs). PLoS One. 2013;8(3):e59116. doi:10.1371/jour-nal.pone.0059116.
Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, et al. Raf family kinases: old dogs have learned new tricks. Genes Cancer. 2011;2:232–60. doi:10.1177/1947601911407323.
Montico B, Colizzi F, Giurato G, Rizzo A, Salvati A, Baboci L, et al. Loss of Spry1 reduces growth of BRAFV600-mutant cutaneous melanoma and improves response to targeted therapy. Cell Death Dis. 2020;11(5):392. doi:10.1038/s41419-020-2585-y.
Pattison MJ, Mitchell O, Flynn HR, Chen C-S, Yang H-T, Ben-Addi H, et al. TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. Biochem J. 2016;473:2845– 61. doi:10.1042/BCJ20160502.
Robinson MJ, Beinke S, Kouroumalis A, Tsichlis PN, Ley SC. Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extra-cellular signal-regulated kinase in mac-rophages. Mol Cell Biol. 2007;27:7355–64. doi:10.1128/MCB.00301-07.
Roget K, Ben-Addi A, Mambole-Dema A, Gantke T, Yang H-T, Janzen J, et al. IκB kinase 2 regulates TPL2 activa-tion of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400. Mol Cell Biol. 2012;32:4684–90. doi:10.1128/MCB.01065-12.
Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J. 1996;15:817–26.
Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M, et al. Mammalian sprouty4 suppresses Rasindependent ERK activation by binding to Raf1. Cell Cycle. 2003;2:281–2.
Schaaf G, Hamdi M, Zwijnenburg D, Lakeman A, Geerts D, Versteeg R, et al. Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene. Cancer Res. 2010;70:762–71. doi:10.1158/0008-5472.CAN-09-2532.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602. doi:10.1016/s0092-8674(00)81902-9.
Shostak K, Zhang X, Hubert P, Göktuna SI, Jiang Z, Klevernic I, et al. NF-κB-induced KIAA1199 promotes survival through EGFR signalling. Nat Commun. 2014;5:5232. doi:10.1038/ncomms6232.
Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B, et al. ERK activation medi-ates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem. 2002;277:12710–7. doi:10.1074/jbc.M111598200.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98-W102. doi:10.1093/nar/gkx247.
Terrell EM, Morrison DK. Ras-mediated activation of the Raf family kinases. Cold Spring Harb Perspect Med. 2019;9(1):a033746. doi:10.1101/cshper-spect.a033746 Cit-ed in: PubMed; PMID 29358316.
Therrien M, Michaud NR, Rubin GM, Morrison DK. KSR modulates signal propagation within the MAPK cascade. Genes Dev. 1996;10:2684–95. doi:10.1101/gad.10.21.2684.
Tomczak MF, Gadjeva M, Wang YY, Brown K, Maroulakou I, Tsichlis PN, et al. Defective activation of ERK in macrophages lacking the p50/p105 subunit of NF-kappaB is responsible for elevated expression of IL-12 p40 observed after challenge with Helicobacter hepaticus. J Immunol. 2006;176:1244–51. doi:10.4049/jimmunol.176.2.1244.
Verlhac MH, Lefebvre C, Kubiak JZ, Umbhauer M, Rassinier P, Colledge W, et al. Mos activates MAP kinase in mouse oocytes through two opposite pathways. EMBO J. 2000;19:6065–74. doi:10.1093/em-boj/19.22.6065.
Virla D, Tsatsanis C, Eliopoulos AG. TPL2. In: Choi S (ed): Encyclopedia of signaling molecules (pp 225-43). Cham: Springer, 2018. doi:10.1007/978-3-319-67199-4_626.
Voigt S, Sterz KR, Giehler F, Mohr A-W, Wilson JB, Moosmann A, et al. A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation. Nat Commun. 2020;11(1):685. doi:10.1038/s41467-020-14502-x.
Wang X, Studzinski GP. Oncoprotein Cot1 represses kinase suppressors of Ras1/2 and 1,25-dihydroxyvita-min D3-induced differentiation of human acute myeloid leukemia cells. J Cell Physiol. 2011;226:1232–40. doi:10.1002/jcp.22449.
Xie X, Zhang D, Zhao B, Lu M-K, You M, Condorelli G, et al. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011;108:6474–9. doi:10.1073/pnas.1016132108.
Xu D, Matsumoto ML, McKenzie BS, Zarrin AA. TPL2 kinase action and control of inflammation. Pharmacol Res. 2018;129:188–93. doi:10.1016/j.phrs.2017.11.031.
Xu S, Robbins D, Frost J, Dang A, Lange-Carter C, Cobb MH. MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1995;92:6808– 12. doi:10.1073/pnas.92.15.6808.
Yin M, Wang X, Lu J. Advances in IKBKE as a potential target for cancer therapy. Cancer Med. 2020;9:247–58. doi:10.1002/cam4.2678.