Volume 11 Issue 11
Nov.  2020
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Weiwei Jiang, Fangfang Cai, Huangru Xu, Yanyan Lu, Jia Chen, Jia Liu, Nini Cao, Xiangyu Zhang, Xiao Chen, Qilai Huang, Hongqin Zhuang, Zi-Chun Hua. Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner[J]. Protein&Cell, 2020, 11(11): 825-845. doi: 10.1007/s13238-020-00701-1
Citation: Weiwei Jiang, Fangfang Cai, Huangru Xu, Yanyan Lu, Jia Chen, Jia Liu, Nini Cao, Xiangyu Zhang, Xiao Chen, Qilai Huang, Hongqin Zhuang, Zi-Chun Hua. Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner[J]. Protein&Cell, 2020, 11(11): 825-845. doi: 10.1007/s13238-020-00701-1

Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner

doi: 10.1007/s13238-020-00701-1

This study was supported by grants from the Chinese National Natural Sciences Foundation (81773099, 81570790), the National Key R&D Program of China (2017YFA0506000).

  • Received Date: 2019-12-03
  • Rev Recd Date: 2020-02-09
  • This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma. We show that ERK5 expression is abundant in human lung cancer samples, and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential. Importantly, we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser910 site. Mechanistically, ERK5 increased the expression of the transcription factor USF1, which could transcriptionally upregulate FAK expression, resulting in FAK signaling activation to promote cell migration. We also provided evidence that the phosphorylation of FAK at Ser910 was due to ERK5 but not ERK1/2, and we then suggested a role for Ser910 in the control of cell motility. In addition, ERK5 had targets in addition to FAK that regulate epithelial-to-mesenchymal transition and cell motility in cancer cells. Taken together, our findings uncover a cancer metastasis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.
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  • [1]
    Brami-Cherrier K, Gervasi N, Arsenieva D, Walkiewicz K, Boutterin MC, Ortega A, Leonard PG, Seantier B, Gasmi L, Bouceba T et al(2014) FAK dimerization controls its kinase-dependent functions at focal adhesions. EMBO J 33:356-370
    Cai X, Lietha D, Ceccarelli DF, Karginov AV, Rajfur Z, Jacobson K, Hahn KM, Eck MJ, Schaller MD (2008) Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol 28:201-214
    Chen R, Yang Q, Lee JD (2012) BMK1 kinase suppresses epithelialmesenchymal transition through the Akt/GSK3beta signaling pathway. Cancer Res 72:1579-1587
    Chen X, Li W, Xu C, Wang J, Zhu B, Huang Q, Chen D, Sheng J, Zou Y, Lee YM et al (2018) Comparative profiling of analog targets:a case study on resveratrol for mouse melanoma metastasis suppression. Theranostics 8:3504-3516
    Choi H, Nesvizhskii AI (2008) False discovery rates and related statistical concepts in mass spectrometry-based proteomics. J Proteome Res 7:47-50
    Dai J, Wang T, Wang W, Zhang S, Liao Y, Chen J (2015) Role of MAPK7 in cell proliferation and metastasis in ovarian cancer. Int J Clin Exp Pathol 8:10444-10451
    Geng H, Zhao L, Liang Z, Zhang Z, Xie D, Bi L, Wang Y, Zhang T, Cheng L, Yu D et al (2015) ERK5 positively regulates cigarette smokeinduced urocystic epithelial-mesenchymal transition in SV40 immortalized human urothelial cells. Oncol Rep 34:1581-1588
    Golubovskaya VM (2010) Focal adhesion kinase as a cancer therapy target. Anticancer Agents Med Chem 10:735-741
    Grigera PR, Jeffery ED, Martin KH, Shabanowitz J, Hunt DF, Parsons JT (2005) FAK phosphorylation sites mapped by mass spectrometry. J Cell Sci 118:4931-4935
    Guarino M, Rubino B, Ballabio G (2007) The role of epithelialmesenchymal transition in cancer pathology. Pathology 39:305-318
    Hanks SK, Ryzhova L, Shin NY, Brabek J (2003) Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci 8:d982-996
    Hao H, Naomoto Y, Bao X, Watanabe N, Sakurama K, Noma K, Motoki T, Tomono Y, Fukazawa T, Shirakawa Y et al (2009) Focal adhesion kinase as potential target for cancer therapy (Review). Oncol Rep 22:973-979
    Hayashi M, Fearns C, Eliceiri B, Yang Y, Lee JD (2005) Big mitogenactivated protein kinase 1/extracellular signal-regulated kinase 5 signaling pathway is essential for tumor-associated angiogenesis. Cancer Res 65:7699-7706
    Hoang VT, Yan TJ, Cavanaugh JE, Flaherty PT, Beckman BS, Burow ME (2017) Oncogenic signaling of MEK5-ERK5. Cancer Lett 392:51-59
    Hunger-Glaser I, Fan RS, Perez-Salazar E, Rozengurt E (2004) PDGF and FGF induce focal adhesion kinase (FAK) phosphorylation at Ser-910:dissociation from Tyr-397 phosphorylation and requirement for ERK activation. J Cell Physiol 200:213-222
    Hunger-Glaser I, Salazar EP, Sinnett-Smith J, Rozengurt E (2003) Bombesin, lysophosphatidic acid, and epidermal growth factor rapidly stimulate focal adhesion kinase phosphorylation at Ser-910:requirement for ERK activation. J Biol Chem 278:22631-22643
    Im JY, Yoon SH, Kim BK, Ban HS, Won KJ, Chung KS, Jung KE, Won M (2016) DNA damage induced apoptosis suppressor(DDIAS) is upregulated via ERK5/MEF2B signaling and promotes beta-catenin-mediated invasion. Biochim Biophys Acta 1859:1449-1458
    Javaid S, Zhang J, Smolen GA, Yu M, Wittner BS, Singh A, Arora KS, Madden MW, Desai R, Zubrowski MJ et al (2015) MAPK7 Regulates EMT Features and Modulates the Generation of CTCs. Mol Cancer Res 13:934-943
    Jiang W, Jin G, Cai F, Chen X, Cao N, Zhang X, Liu J, Chen F, Wang F, Dong W et al (2019) Extracellular signal-regulated kinase 5 increases radioresistance of lung cancer cells by enhancing the DNA damage response. Exp Mol Med 51:19
    Kleinschmidt EG, Schlaepfer DD (2017) Focal adhesion kinase signaling in unexpected places. Curr Opin Cell Biol 45:24-30
    Lauffenburger DA, Horwitz AF (1996) Cell migration:a physically integrated molecular process. Cell 84:359-369
    Lechertier T, Hodivala-Dilke K (2012) Focal adhesion kinase and tumour angiogenesis. J Pathol 226:404-412
    Lee BY, Timpson P, Horvath LG, Daly RJ (2015) FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther 146:132-149
    Li S, Dong W, Zong Y, Yin W, Jin G, Hu Q, Huang X, Jiang W, Hua ZC (2007) Polyethylenimine-complexed plasmid particles targeting focal adhesion kinase function as melanoma tumor therapeutics. Mol Ther 15:515-523
    Liang Z, Wu R, Xie W, Xie C, Wu J, Geng S, Li X, Zhu M, Zhu W, Zhu J et al (2017) Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal Transition In Vivo. Phytother Res 31:1230-1239
    Liang Z, Xie W, Wu R, Geng H, Zhao L, Xie C, Li X, Huang C, Zhu J, Zhu M et al (2015a) ERK5 negatively regulates tobacco smokeinduced pulmonary epithelial-mesenchymal transition. Oncotarget 6:19605-19618
    Liang Z, Xie W, Wu R, Geng H, Zhao L, Xie C, Li X, Zhu M, Zhu W, Zhu J et al (2015b) Inhibition of tobacco smoke-induced bladder MAPK activation and epithelial-mesenchymal transition in mice by curcumin. Int J Clin Exp Pathol 8:4503-4513
    Lin Y, Peng N, Li J, Zhuang H, Hua ZC (2013) Herbal compound triptolide synergistically enhanced antitumor activity of aminoterminal fragment of urokinase. Mol Cancer 12:54
    Liu F, Zhang H, Song H (2017) Upregulation of MEK5 by Stat3
    promotes breast cancer cell invasion and metastasis. Oncol Rep 37:83-90
    Ma A, Richardson A, Schaefer EM, Parsons JT (2001) Serine phosphorylation of focal adhesion kinase in interphase and mitosis:a possible role in modulating binding to p130(Cas). Mol Biol Cell 12:1-12
    Mehta PB, Jenkins BL, McCarthy L, Thilak L, Robson CN, Neal DE, Leung HY (2003) MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. Oncogene 22:1381-1389
    Min J, Geng H, Liu Z, Liang Z, Zhang Z, Xie D, Wang Y, Zhang T, Yu D, Zhong C (2017) ERK5 regulates tobacco smokeinduced urocystic epithelialmesenchymal transition in BALB/c mice. Mol Med Rep 15:3893-3897
    Mody N, Campbell DG, Morrice N, Peggie M, Cohen P (2003) An analysis of the phosphorylation and activation of extracellular-signalregulated protein kinase 5(ERK5) by mitogen-activated protein kinase kinase 5(MKK5) in vitro. Biochemical Journal 372:567-575
    Park SJ, Choi YS, Lee S, Lee YJ, Hong S, Han S, Kim BC (2016) BIX02189 inhibits TGF-beta1-induced lung cancer cell metastasis by directly targeting TGF-beta type I receptor. Cancer Lett 381:314-322
    Parsons JT (2003) Focal adhesion kinase:the first ten years. J Cell Sci 116:1409-1416
    Provenzano PP, Keely PJ (2009) The role of focal adhesion kinase in tumor initiation and progression. Cell Adh Migr 3:347-350
    Ramsay AK, McCracken SR, Soofi M, Fleming J, Yu AX, Ahmad I, Morland R, Machesky L, Nixon C, Edwards DR et al (2011) ERK5 signalling in prostate cancer promotes an invasive phenotype. Br J Cancer 104:664-672
    Rovida E, Di Maira G, Tusa I, Cannito S, Paternostro C, Navari N, Vivoli E, Deng X, Gray NS, Esparis-Ogando A et al (2015) The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma. Gut 64:1454-1465
    Salinas-Sanchez AS, Serrano-Oviedo L, Nam-Cha SY, RocheLosada O, Sanchez-Prieto R, Gimenez-Bachs JM (2017) Prognostic Value of the VHL, HIF-1alpha, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study. Clin Genitourin Cancer 15:e923-e933
    Sawhney RS, Liu W, Brattain MG (2009) A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling. J Cell Physiol 219:152-161
    Schaller MD (2010) Cellular functions of FAK kinases:insight into molecular mechanisms and novel functions. J Cell Sci 123:1007-1013
    Shilov IV, Seymour SL, Patel AA, Loboda A, Tang WH, Keating SP, Hunter CL, Nuwaysir LM, Schaeffer DA (2007) The Paragon Algorithm, a next generation search engine that uses sequence temperature values and feature probabilities to identify peptides from tandem mass spectra. Mol Cell Proteomics 6:1638-1655
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7-30
    Sticht C, Freier K, Knopfle K, Flechtenmacher C, Pungs S, Hofele C, Hahn M, Joos S, Lichter P (2008) Activation of MAP kinase signaling through ERK5 but not ERK1 expression is associated with lymph node metastases in oral squamous cell carcinoma(OSCC). Neoplasia 10:462-470
    Tang WH, Shilov IV, Seymour SL (2008) Nonlinear fitting method for determining local false discovery rates from decoy database searches. J Proteome Res 7:3661-3667
    Umapathy G, El Wakil A, Witek B, Chesler L, Danielson L, Deng X, Gray NS, Johansson M, Kvarnbrink S, Ruuth K et al (2014) The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma. Sci Signal 7(349):102
    Villa-Moruzzi E (2007) Targeting of FAK Ser910 by ERK5 and PP1delta in non-stimulated and phorbol ester-stimulated cells. Biochem J 408:7-18
    Villa-Moruzzi E (2011) Tyrosine phosphatases in the HER2-directed motility of ovarian cancer cells:Involvement of PTPN12, ERK5 and FAK. Anal Cell Pathol (Amst) 34:101-112
    Wang ZY, Wang WJ, Xu S, Wang SS, Tu Y, Xiong YF, Mei JH, Wang CL (2016) The role of MAPK signaling pathway in the Her-2-positive meningiomas. Oncology Reports 36:685-695
    Won KJ, Im JY, Kim BK, Ban HS, Jung YJ, Jung KE, Won M (2017) Stability of the cancer target DDIAS is regulated by the CHIP/HSP70 pathway in lung cancer cells. Cell Death Dis 8:e2554
    Wright TD, Raybuck C, Bhatt A, Monlish D, Chakrabarty S, Wendekier K, Gartland N, Gupta M, Burow ME, Flaherty PT et al (2020) Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer. J Cell Biochem 121:1156-1168
    Wu J, Cui H, Zhu Z, Wang L (2016) MicroRNA-200b-3p suppresses epithelial-mesenchymal transition and inhibits tumor growth of glioma through down-regulation of ERK5. Biochem Biophys Res Commun 478:1158-1164
    Yoon H, Dehart JP, Murphy JM, Lim ST (2015) Understanding the roles of FAK in cancer:inhibitors, genetic models, and new insights. J Histochem Cytochem 63:114-128
    Zhao X, Guan JL (2011) Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev 63:610-615
    Zhu Y, Casado M, Vaulont S, Sharma K (2005) Role of upstream stimulatory factors in regulation of renal transforming growth factor-beta1. Diabetes 54:1976-1984
    Zhuang K, Zhang J, Xiong M, Wang X, Luo X, Han L, Meng Y, Zhang Y, Liao W, Liu S (2016) CDK5 functions as a tumor promoter in human colorectal cancer via modulating the ERK5-AP-1 axis. Cell Death Dis 7:e2415
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