IL-1β-activated PI3K/AKT and MEK/ERK pathways coordinately promote induction of partial epithelial-mesenchymal transition.
Epithelial–mesenchymal transition
Interleukin-1β
MEK/ERK pathway
PI3K/AKT pathway
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
08 Aug 2024
08 Aug 2024
Historique:
received:
31
05
2024
accepted:
01
08
2024
medline:
9
8
2024
pubmed:
9
8
2024
entrez:
8
8
2024
Statut:
epublish
Résumé
Epithelial-mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1β (IL-1β) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1β-mediated EMT are not yet completely understood. Here, we found that IL-1β stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1β-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1β-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1β-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis.
Identifiants
pubmed: 39118068
doi: 10.1186/s12964-024-01775-8
pii: 10.1186/s12964-024-01775-8
doi:
Substances chimiques
Interleukin-1beta
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
392Subventions
Organisme : Japan Society for the Promotion of Science
ID : 19K12351
Organisme : Japan Society for the Promotion of Science
ID : 21H02083
Informations de copyright
© 2024. The Author(s).
Références
Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21:341–52.
pubmed: 32300252
pmcid: 7250738
doi: 10.1038/s41580-020-0237-9
Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.
pubmed: 19945376
doi: 10.1016/j.cell.2009.11.007
Sisto M, Ribatti D, Lisi S. Organ fibrosis and autoimmunity: the role of inflammation in TGFβ-dependent EMT. Biomolecules. 2021;11:310.
pubmed: 33670735
pmcid: 7922523
doi: 10.3390/biom11020310
Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4:6.
pubmed: 25852822
pmcid: 4385028
doi: 10.1186/s40169-015-0048-3
Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–37.
pubmed: 19487819
pmcid: 2689132
doi: 10.1172/JCI36183
Stone RC, Pastar I, Ojeh N, Chen V, Liu S, Garzon KI, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 2016;365:495–506.
pubmed: 27461257
pmcid: 5011038
doi: 10.1007/s00441-016-2464-0
Leggett SE, Hruska AM, Guo M, Wong IY. The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems. Cell Commun Signal. 2021;19:32.
pubmed: 33691719
pmcid: 7945251
doi: 10.1186/s12964-021-00713-2
Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. Tumor budding: the name is EMT Partial EMT. J Clin Med. 2016;5:51.
pubmed: 27136592
pmcid: 4882480
doi: 10.3390/jcm5050051
Jolly MK, Ware KE, Gilja S, Somarelli JA, Levine H. EMT and MET: necessary or permissive for metastasis? Mol Oncol. 2017;11:755–69.
pubmed: 28548345
pmcid: 5496498
doi: 10.1002/1878-0261.12083
Aiello NM, Kang Y. Context-dependent EMT programs in cancer metastasis. J Exp Med. 2019;216:1016–26.
pubmed: 30975895
pmcid: 6504222
doi: 10.1084/jem.20181827
Nieto MA, Huang RYJ, Jackson RA, Thiery JPEMT. Cell. 2016;2016(166):21–45.
doi: 10.1016/j.cell.2016.06.028
Sheng L, Zhuang S. New insights into the role and mechanism of partial epithelial-mesenchymal transition in kidney fibrosis. Front Physiol. 2020;11:569322.
pubmed: 33041867
pmcid: 7522479
doi: 10.3389/fphys.2020.569322
Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am J Pathol. 2005;166:1321–32.
pubmed: 15855634
pmcid: 1606388
doi: 10.1016/S0002-9440(10)62351-6
Jolly MK, Boareto M, Huang B, Jia D, Lu M, Ben-Jacob E, et al. Implication of the hybrid epithelial/mesenchymal phenotype in metastasis. Front Oncol. 2015;5:155.
pubmed: 26258068
pmcid: 4507461
doi: 10.3389/fonc.2015.00155
Aggarwal V, Montoya CA, Donnenberg VS, Sant S. Interplay between microenvironment and partial EMT as the driver of tumor progression. iScience. 2021;24:102113.
pubmed: 33659878
pmcid: 7892926
doi: 10.1016/j.isci.2021.102113
Papadaki MA, Stoupis G, Theodoropoulos PA, Mavroudis D, Georgoulias V, Agelaki S. Circulating tumor cells with stemness and epithelial-to-mesenchymal transition features are chemoresistant and predictive of poor outcome in metastatic breast cancer. Mol Cancer Ther. 2019;18:437–47.
pubmed: 30401696
doi: 10.1158/1535-7163.MCT-18-0584
Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17:545–58.
pubmed: 28580957
pmcid: 5753586
doi: 10.1038/nri.2017.52
López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1:303–14.
pubmed: 20049734
pmcid: 3378143
doi: 10.1002/emmm.200900043
Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol. 2017;11:805–23.
pubmed: 28599100
pmcid: 5496491
doi: 10.1002/1878-0261.12095
Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, et al. Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 2007;26:7445–56.
pubmed: 17563753
doi: 10.1038/sj.onc.1210546
Yadav A, Kumar B, Datta J, Teknos TN, Kumar P. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res. 2011;9:1658–67.
pubmed: 21976712
pmcid: 3243808
doi: 10.1158/1541-7786.MCR-11-0271
Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res. 2011;71:5296–306.
pubmed: 21653678
pmcid: 3148346
doi: 10.1158/0008-5472.CAN-11-0156
Fu XT, Dai Z, Song K, Zhang ZJ, Zhou ZJ, Zhou SL, et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating JAK2/STAT3/Snail pathway. Int J Oncol. 2015;46:587–96.
pubmed: 25405790
doi: 10.3892/ijo.2014.2761
Deng F, Weng Y, Li X, Wang T, Fan M, Shi Q. Overexpression of IL-8 promotes cell migration via PI3K-Akt signaling pathway and EMT in triple-negative breast cancer. Pathol Res Pract. 2020;216:15292.
doi: 10.1016/j.prp.2020.152902
Tabei Y, Yokota K, Nakajima Y. Interleukin-1β released from macrophages stimulated with indium tin oxide nanoparticles induced epithelial mesenchymal transition in A549 cells. Environ Sci Nano. 2022;9:1489–508.
doi: 10.1039/D2EN00031H
Li Y, Wang L, Pappan L, Galliher-Beckley A, Shi J. IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol Cancer. 2012;11:87.
pubmed: 23174018
pmcid: 3532073
doi: 10.1186/1476-4598-11-87
Lee CH, Chang JSM, Syu SH, Wong TS, Chan JYW, Tang YC, et al. IL-1β promotes malignant transformation and tumor aggressiveness in oral cancer. J Cell Physiol. 2015;230:875–84.
pubmed: 25204733
doi: 10.1002/jcp.24816
Li R, Ong SL, Tran LM, Jing Z, Liu B, Park SJ, et al. Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer. Sci Rep. 2020;10:377.
pubmed: 31941995
pmcid: 6962381
doi: 10.1038/s41598-019-57285-y
Fang Z, Grütter C, Rauh D. Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol. 2013;8:58–70.
pubmed: 23249378
doi: 10.1021/cb300663j
Harris VM. Protein detection by Simple Western™ analysis. Methods Mol Biol. 2015;1312:465–8.
pubmed: 26044028
doi: 10.1007/978-1-4939-2694-7_47
Tabei Y, Abe H, Suzuki S, Takeda N, Arai JI, Nakajima Y. Sedanolide activates KEAP1-NRF2 pathway and ameliorates hydrogen peroxide-induced apoptotic cell death. Int J Mol Sci. 2023;24:16532.
pubmed: 38003720
pmcid: 10671709
doi: 10.3390/ijms242216532
Pastushenko I, Blanpain C. EMT transition state during tumor progression and metastasis. Trends Cell Biol. 2019;29:212–26.
pubmed: 30594349
doi: 10.1016/j.tcb.2018.12.001
Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol. 2007;293:L525–35.
pubmed: 17631612
doi: 10.1152/ajplung.00163.2007
Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal. 2010;3:cm1.
pubmed: 20086235
Cheng CY, Kuo CT, Lin CC, Hsieh HL, Yang CM. IL-1beta induces expression of matrix metalloproteinase-9 and cell migration via a c-Src-dependent, growth factor receptor transactivation in A549 cells. Br J Pharmacol. 2010;160:1595–610.
pubmed: 20649564
pmcid: 2936833
doi: 10.1111/j.1476-5381.2010.00858.x
Goh LK, Sorkin A. Endocytosis of receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5:a017459.
pubmed: 23637288
pmcid: 3632065
doi: 10.1101/cshperspect.a017459
Sanchez-Guerrero E, Chen E, Kockx M, An SW, Chong BH, Khachigian LM. IL-1beta signals through the EGF receptor and activates Egr-1 through MMP-ADAM. PLoS ONE. 2012;7:e39811.
pubmed: 22792188
pmcid: 3391205
doi: 10.1371/journal.pone.0039811
Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278:16–27.
pubmed: 21087457
doi: 10.1111/j.1742-4658.2010.07919.x
Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53.
pubmed: 29455669
pmcid: 5817859
doi: 10.1186/s12943-018-0793-1
Yotsumoto F, Fukagawa S, Miyata K, Nam SO, Katsuda T, Miyahara D, et al. HB-EGF is a promising therapeutic target for lung cancer with secondary mutation of EGFR
pubmed: 28668882
Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.
pubmed: 19302047
doi: 10.1146/annurev.immunol.021908.132612
Pearson G, Robinson F, Gibson TB, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–83.
pubmed: 11294822
Fu L, Chen S, He G, Chen Y, Liu B. Targeting extracellular signal-regulated protein kinase 1/2 (ERK1/2) in cancer: An update on pharmacological small-molecule inhibitors. J Med Chem. 2022;65:13561–73.
pubmed: 36205714
doi: 10.1021/acs.jmedchem.2c01244
Gantke T, Sriskantharajah S, Sadowski M, Ley SC. IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunol Rev. 2012;246:168–82.
pubmed: 22435554
doi: 10.1111/j.1600-065X.2012.01104.x
Ben-Addi A, Mambole-Dema A, Brender C, Martin SR, Janzen J, Kjaer S, Smerdon SJ, et al. IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases. Proc Natl Acad Sci U S A. 2014;111:E2394–403.
pubmed: 24912162
pmcid: 4060680
doi: 10.1073/pnas.1320440111
Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7:re8.
pubmed: 25249658
pmcid: 4372086
doi: 10.1126/scisignal.2005189
Zhang J, Tian XJ, Zhang H, Teng Y, Li R, Bai F. TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci Signal. 2014;7:ra91.
pubmed: 25270257
doi: 10.1126/scisignal.2005304
Liarte S, Bernabé-García Á, Nicolás FJ. Human skin keratinocytes on sustained TGF-β stimulation reveal partial EMT features and weaken growth arrest responses. Cells. 2020;9:255.
pubmed: 31968599
pmcid: 7017124
doi: 10.3390/cells9010255
Lundgren K, Nordenskjöld B, Landberg G. Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer. Br J Cancer. 2009;101:1769–81.
pubmed: 19844232
pmcid: 2778529
doi: 10.1038/sj.bjc.6605369
Villanueva-Duque A, Zuniga-Eulogio MD, Dena-Beltran J, Castaneda-Saucedo E, Calixto-Galvez M, Mendoza-Catalán MA, et al. Leptin induces partial epithelial-mesenchymal transition in a FAK-ERK dependent pathway in MCF10A mammary non-tumorigenic cell. Int J Clin Exp Pathol. 2017;10:10334–42.
pubmed: 31966368
pmcid: 6965759
Hackel PO, Zwick E, Prenzel N, Ullrich A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol. 1999;11:184–9.
pubmed: 10209149
doi: 10.1016/S0955-0674(99)80024-6
Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor. Curr Opin Cell Biol. 1999;11:190–6.
pubmed: 10209155
doi: 10.1016/S0955-0674(99)80025-8
Zandi R, Larsen AB, Andersen P, Stockhausen MT, Poulsen HS. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal. 2007;19:2013–23.
pubmed: 17681753
doi: 10.1016/j.cellsig.2007.06.023
Chen J, Zeng F, Forrester SJ, Eguchi S, Zhang MZ, Harris RC. Expression and function of the epidermal growth factor receptor in physiology and disease. Physiol Rev. 2016;96:1025–69.
pubmed: 33003261
doi: 10.1152/physrev.00030.2015
Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21:177–84.
doi: 10.1016/j.ceb.2008.12.010
Higashiyama S, Nanba D, Nakayama H, Inoue H, Fukuda S. Ectodomain shedding and remnant peptide signaling of EGFRs and their ligands. J Biochem. 2011;150:15–22.
pubmed: 21610047
doi: 10.1093/jb/mvr068
Liebmann C. EGF receptor activation by GPCRs: an universal pathway reveals different versions. Mol Cell Endocrinol. 2011;331:222–31.
pubmed: 20398727
doi: 10.1016/j.mce.2010.04.008
Matsuo M, Sakurai H, Ueno Y, Ohtani O, Saiki I. Activation of MEK/ERK and PI3K/Akt pathways by fibronectin requires integrin αv-mediated ADAM activity in hepatocellalr carcinoma: a novel functional target for gefitinib. Cancer Sci. 2006;97:155–62.
pubmed: 16441427
pmcid: 11159791
doi: 10.1111/j.1349-7006.2006.00152.x
Vara JAF, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signaling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.
doi: 10.1016/j.ctrv.2003.07.007
Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene. 2005;24:7443–54.
pubmed: 16288291
doi: 10.1038/sj.onc.1209091
Maharati A, Moghbeli M. PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells. Cell Commun Signal. 2023;21:201.
pubmed: 37580737
pmcid: 10424373
doi: 10.1186/s12964-023-01225-x
Wang H, Wang HS, Zhou BH, Li CL, Zhang F, Wang XF, et al. Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer. PLoS ONE. 2013;8:e56664.
pubmed: 23431386
pmcid: 3576347
doi: 10.1371/journal.pone.0056664
Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 2013;4:e875.
pubmed: 24157869
pmcid: 3920940
doi: 10.1038/cddis.2013.407
Chen S, Yang Y, Zheng Z, Zhang M, Chen X, Xiao N, et al. IL-1β promotes esophageal squamous cell carcinoma growth and metastasis through FOXO3A by activating the PI3K/AKT pathway. Cell Death Discov. 2024;10:238.
pubmed: 38762529
pmcid: 11102492
doi: 10.1038/s41420-024-02008-0
Jaramillo ML, Banville M, Collins C, Paul-Roc B, Bourget L, O’Connor-McCourt M. Differential sensitivity of A549 non-small lung carcinoma cell responses to epidermal growth factor receptor pathway inhibitors. Cancer Biol Ther. 2008;7:557–68.
pubmed: 18296914
doi: 10.4161/cbt.7.4.5533
Liu ZC, Chen XH, Song HX, Wang HS, Zhang G, Wang H, et al. Snail regulated by PKC/GSK-3β pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res. 2014;358:491–502.
pubmed: 25124796
doi: 10.1007/s00441-014-1953-2
Lauand C, Rezende-Teixeira P, Cortez BA, Niero EL, Machado-Santelli GM. Independent of ErbB1 gene copy number, EGF stimulates migration but not associated with cell proliferation in non-small cell lung cancer. Cancer Cell Int. 2013;13:38.
pubmed: 23631593
pmcid: 3655000
doi: 10.1186/1475-2867-13-38
Schelch K, Vogel L, Schneller A, Brankovic J, Mohr T, Mayer RL, et al. EGF induces migration independent of EMT or invasion in A549 lung adenocarcinoma cells. Front Cell Dev Biol. 2021;9:634371.
pubmed: 33777943
pmcid: 7994520
doi: 10.3389/fcell.2021.634371
Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007;117:3786–99.
pubmed: 17992263
pmcid: 2066195
Yang W, Bai X, Luan X, Min J, Tian X, Li H, et al. Delicate regulation of IL-1β-mediated inflammation by cyclophilin A. Cell Rep. 2022;38:110513.
pubmed: 35294882
doi: 10.1016/j.celrep.2022.110513
Zou M, Zhang G, Zou J, Liu Y, Liu B, Hu X, et al. Inhibition of the ERK1/2-ubiquitas calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro. Exp Cell Res. 2020;391: 111886.
pubmed: 32017927
doi: 10.1016/j.yexcr.2020.111886
Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007;1773:1213–26.
pubmed: 17112607
doi: 10.1016/j.bbamcr.2006.10.005
Yang L, Zheng L, Chng WJ, Ding JL. Comprehensive analysis of ERK1/2 substrates for potential combination immunotherapies. Trends Pharmacol Sci. 2019;40:897–910.
pubmed: 31662208
doi: 10.1016/j.tips.2019.09.005
Tripathi K, Garg M. Mechanistic regulation of epithelial-to-mesenchymal transition through RAS signaling pathway and therapeutic implication in human cancer. J Cell Commun Signal. 2018;12:513–27.
pubmed: 29330773
pmcid: 6039341
doi: 10.1007/s12079-017-0441-3
Martin-Vega A, Cobb MH. Navigating the ERK1/2 MAPK cascade. Biomolecules. 2023;13:1555.
pubmed: 37892237
pmcid: 10605237
doi: 10.3390/biom13101555
Rodríguez C, Pozo M, Nieto E, Fernández M, Alemany S. TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cell Signal. 2006;18:1376–85.
pubmed: 16371247
doi: 10.1016/j.cellsig.2005.10.016
Xu D, Matsumoto ML, McKenzie BS, Zarrin AA. TPL2 kinase action and control of inflammation. Pharmacol Res. 2018;129:188–93.
pubmed: 29183769
doi: 10.1016/j.phrs.2017.11.031
Perugorria MJ, Murphy LB, Fullard N, Chakraborty JB, Vyrla D, Wilson CL, et al. Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor-induced TIMP-1 gene transcription in hepatic stellate cells in mice. Hepatology. 2013;57:1238–49.
pubmed: 23080298
doi: 10.1002/hep.26108
Kim K, Kim G, Kim JY, Yun HJ, Lim SC, Coi HS, et al. Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation. Carcinogenesis. 2014;35:1352–61.
pubmed: 24517997
doi: 10.1093/carcin/bgu044
Lee HW, Cho HJ, Lee SJ, Song LH, Cho HJ, Park MC, et al. Tpl2 induces castration resistant prostate cancer progression and metastasis. Int J Cancer. 2015;136:2065–77.
pubmed: 25274482
doi: 10.1002/ijc.29248
Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, et al. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114:569–81.
pubmed: 15314694
pmcid: 503772
doi: 10.1172/JCI200421358
Li Q, Li Z, Luo T, Shi H. Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy. Mol Biomed. 2022;3:47.
pubmed: 36539659
pmcid: 9768098
doi: 10.1186/s43556-022-00110-2
De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signaling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012;16(Suppl 2):S17-27.
pubmed: 22443084
doi: 10.1517/14728222.2011.639361
Cao Z, Liao Q, Su M, Huang K, Jin J, Cao D. AKT and ERK dual inhibitors: The way forward? Cancer Lett. 2019;459:30–40.
pubmed: 31128213
doi: 10.1016/j.canlet.2019.05.025
Ruhul Amin ARM, Senga T, Oo ML, Thant AA, Hamaguchi M. Secretion of matrix metalloproteinase-9 by the proinflammatory cytokine, IL-1β: a role for the dual signalling pathways. Akt and Erk Genes Cells. 2003;8:515–23.
pubmed: 12786942
doi: 10.1046/j.1365-2443.2003.00652.x
Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–8.
pubmed: 21531565
pmcid: 3112285
doi: 10.1016/j.tibs.2011.03.006
Pacold ME, Suire S, Peerisic O, Lara-Gonzalez S, Davis CT, Walker EH, et al. Crystal structure and functional analysis f Ras binding to its effector phosphoinositide 3-kinase γ. Cell. 2000;103:931–43.
pubmed: 11136978
doi: 10.1016/S0092-8674(00)00196-3
Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999;286:1741–4.
pubmed: 10576742
doi: 10.1126/science.286.5445.1741
Dodhiawala PB, Khurana N, Zhang D, Cheng Y, Li Lin, Wei Q, et al. TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations. J Clin Invest. 2020;130:4771–90.
pubmed: 32573499
pmcid: 7456254
doi: 10.1172/JCI137660
Waterfield M, Jin W, Reiley W, Zhang M, Sun SC. IκB kinase is an essential component of the Tpl2 signaling pathway. Mol Cell Biol. 2004;24:6040–8.
pubmed: 15199157
pmcid: 480897
doi: 10.1128/MCB.24.13.6040-6048.2004
He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6:425.
pubmed: 34916492
pmcid: 8677728
doi: 10.1038/s41392-021-00828-5