Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.

Laboratory of Structural Biology and Cell Signaling Institute of Microbiology of the Czech Academy of Sciences 14220 Prague Czech Republic

Zobrazit více v PubMed

Widmann C., Gibson S., Jarpe M.B., Johnson G.L. Mitogen-activated protein kinase: Conservation of a three-kinase module from yeast to human. Physiol. Rev. 1999;79:143–180. doi: 10.1152/physrev.1999.79.1.143. PubMed DOI

Fey D., Matallanas D., Rauch J., Rukhlenko O.S., Kholodenko B.N. The complexities and versatility of the RAS-to-ERK signalling system in normal and cancer cells. Semin. Cell Dev. Biol. 2016;58:96–107. doi: 10.1016/j.semcdb.2016.06.011. PubMed DOI

Dhillon A.S., Hagan S., Rath O., Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26:3279–3290. doi: 10.1038/sj.onc.1210421. PubMed DOI

Chappell W.H., Steelman L.S., Long J.M., Kempf R.C., Abrams S.L., Franklin R.A., Basecke J., Stivala F., Donia M., Fagone P., et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: Rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011;2:135–164. doi: 10.18632/oncotarget.240. PubMed DOI PMC

Steelman L.S., Chappell W.H., Abrams S.L., Kempf R.C., Long J., Laidler P., Mijatovic S., Maksimovic-Ivanic D., Stivala F., Mazzarino M.C., et al. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging. 2011;3:192–222. doi: 10.18632/aging.100296. PubMed DOI PMC

Oughtred R., Stark C., Breitkreutz B.J., Rust J., Boucher L., Chang C., Kolas N., O’Donnell L., Leung G., McAdam R., et al. The BioGRID interaction database: 2019 update. Nucleic Acids Res. 2019;47:D529–D541. doi: 10.1093/nar/gky1079. PubMed DOI PMC

Tang J., Liao Y., He S., Shi J., Peng L., Xu X., Xie F., Diao N., Huang J., Xie Q., et al. Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling. J. Transl. Med. 2017;15:238. doi: 10.1186/s12967-017-1342-1. PubMed DOI PMC

Yu W., Liao Q.Y., Hantash F.M., Sanders B.G., Kline K. Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. Cancer Res. 2001;61:6569–6576. PubMed

Xu Z., Zhu C., Chen C., Zong Y., Feng H., Liu D., Feng W., Zhao J., Lu A. CCL19 suppresses angiogenesis through promoting miR-206 and inhibiting Met/ERK/Elk-1/HIF-1alpha/VEGF-A pathway in colorectal cancer. Cell Death Dis. 2018;9:974. doi: 10.1038/s41419-018-1010-2. PubMed DOI PMC

Hayes T.K., Neel N.F., Hu C., Gautam P., Chenard M., Long B., Aziz M., Kassner M., Bryant K.L., Pierobon M., et al. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell. 2016;29:75–89. doi: 10.1016/j.ccell.2015.11.011. PubMed DOI PMC

Ciccarelli C., Di Rocco A., Gravina G.L., Mauro A., Festuccia C., Del Fattore A., Berardinelli P., De Felice F., Musio D., Bouche M., et al. Disruption of MEK/ERK/c-Myc signaling radiosensitizes prostate cancer cells in vitro and in vivo. J. Cancer Res. Clin. Oncol. 2018;144:1685–1699. doi: 10.1007/s00432-018-2696-3. PubMed DOI

Ishida C.T., Zhang Y., Bianchetti E., Shu C., Nguyen T.T.T., Kleiner G., Sanchez-Quintero M.J., Quinzii C.M., Westhoff M.A., Karpel-Massler G., et al. Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma. Clin. Cancer Res. 2018;24:5392–5406. doi: 10.1158/1078-0432.CCR-18-1040. PubMed DOI PMC

Yu Z., Ju Y., Liu H. Antilung cancer effect of glucosamine by suppressing the phosphorylation of FOXO. Mol. Med. Rep. 2017;16:3395–3400. doi: 10.3892/mmr.2017.6976. PubMed DOI

Wang J., Liu L., Qiu H., Zhang X., Guo W., Chen W., Tian Y., Fu L., Shi D., Cheng J., et al. Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells. PLoS ONE. 2013;8:e63872. doi: 10.1371/journal.pone.0063872. PubMed DOI PMC

He J., McLaughlin R.P., van der Noord V., Foekens J.A., Martens J.W.M., van Westen G., Zhang Y., van de Water B. Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer. Breast Cancer Res. Treat. 2019;178:263–274. doi: 10.1007/s10549-019-05380-z. PubMed DOI PMC

Zassadowski F., Pokorna K., Ferre N., Guidez F., Llopis L., Chourbagi O., Chopin M., Poupon J., Fenaux P., Ann Padua R., et al. Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent. Leukemia. 2015;29:2277–2284. doi: 10.1038/leu.2015.159. PubMed DOI

Ramkissoon A., Chaney K.E., Milewski D., Williams K.B., Williams R.L., Choi K., Miller A., Kalin T.V., Pressey J.G., Szabo S., et al. Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK. Clin. Cancer Res. 2019;25:4117–4127. doi: 10.1158/1078-0432.CCR-18-3224. PubMed DOI PMC

Jin T., Li D., Yang T., Liu F., Kong J., Zhou Y. PTPN1 promotes the progression of glioma by activating the MAPK/ERK and PI3K/AKT pathways and is associated with poor patient survival. Oncol. Rep. 2019;42:717–725. doi: 10.3892/or.2019.7180. PubMed DOI

Stevens C., Lin Y., Sanchez M., Amin E., Copson E., White H., Durston V., Eccles D.M., Hupp T. A germ line mutation in the death domain of DAPK-1 inactivates ERK-induced apoptosis. J. Biol. Chem. 2007;282:13791–13803. doi: 10.1074/jbc.M605649200. PubMed DOI

Han M., Gao H., Ju P., Gao M.Q., Yuan Y.P., Chen X.H., Liu K.L., Han Y.T., Han Z.W. Hispidulin inhibits hepatocellular carcinoma growth and metastasis through AMPK and ERK signaling mediated activation of PPARgamma. Biomed. Pharmacother. 2018;103:272–283. doi: 10.1016/j.biopha.2018.04.014. PubMed DOI

Wang Z., Wu Y., Wang H., Zhang Y., Mei L., Fang X., Zhang X., Zhang F., Chen H., Liu Y., et al. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc. Natl. Acad. Sci. USA. 2014;111:E89–E98. doi: 10.1073/pnas.1319190110. PubMed DOI PMC

Lian Y.F., Huang Y.L., Zhang Y.J., Chen D.M., Wang J.L., Wei H., Bi Y.H., Jiang Z.W., Li P., Chen M.S., et al. CACYBP Enhances Cytoplasmic Retention of P27(Kip1) to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics. 2019;9:8392–8408. doi: 10.7150/thno.36838. PubMed DOI PMC

Yan S., Li A., Liu Y. CacyBP/SIP inhibits the migration and invasion behaviors of glioblastoma cells through activating Siah1 mediated ubiquitination and degradation of cytoplasmic p27. Cell Biol. Int. 2018;42:216–226. doi: 10.1002/cbin.10889. PubMed DOI

Pan Z.Q. Cullin-RING E3 Ubiquitin Ligase 7 in Growth Control and Cancer. Adv. Exp. Med. Biol. 2020;1217:285–296. doi: 10.1007/978-981-15-1025-0_17. PubMed DOI PMC

Yu Q., Hu Z., Shen Y., Jiang Y., Pan P., Hou T., Pan Z.Q., Huang J., Sun Y. Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes. Neoplasia. 2020;22:179–191. doi: 10.1016/j.neo.2020.02.003. PubMed DOI PMC

Li Z., Pei X.H., Yan J., Yan F., Cappell K.M., Whitehurst A.W., Xiong Y. CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity. Mol. Cell. 2014;54:805–819. doi: 10.1016/j.molcel.2014.03.046. PubMed DOI PMC

Leichner G.S., Avner R., Harats D., Roitelman J. Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation. Mol. Biol. Cell. 2009;20:3330–3341. doi: 10.1091/mbc.e08-09-0953. PubMed DOI PMC

Gastelum G., Poteshkina A., Veena M., Artiga E., Weckstein G., Frost P. Restoration of the prolyl-hydroxylase domain protein-3 oxygen-sensing mechanism is responsible for regulation of HIF2alpha expression and induction of sensitivity of myeloma cells to hypoxia-mediated apoptosis. PLoS ONE. 2017;12:e0188438. doi: 10.1371/journal.pone.0188438. PubMed DOI PMC

Su Y., Loos M., Giese N., Hines O.J., Diebold I., Gorlach A., Metzen E., Pastorekova S., Friess H., Buchler P. PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. Br. J. Cancer. 2010;103:1571–1579. doi: 10.1038/sj.bjc.6605936. PubMed DOI PMC

Hogel H., Rantanen K., Jokilehto T., Grenman R., Jaakkola P.M. Prolyl hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells. PLoS ONE. 2011;6:e27112. doi: 10.1371/journal.pone.0027112. PubMed DOI PMC

Schoepflin Z.R., Silagi E.S., Shapiro I.M., Risbud M.V. PHD3 is a transcriptional coactivator of HIF-1alpha in nucleus pulposus cells independent of the PKM2-JMJD5 axis. FASEB J. 2017;31:3831–3847. doi: 10.1096/fj.201601291R. PubMed DOI PMC

Ma X., Wang X., Cao J., Geng Z., Wang Z. Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway. PLoS ONE. 2014;9:e95692. doi: 10.1371/journal.pone.0095692. PubMed DOI PMC

Hulea L., Gravel S.P., Morita M., Cargnello M., Uchenunu O., Im Y.K., Lehuede C., Ma E.H., Leibovitch M., McLaughlan S., et al. Translational and HIF-1alpha-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides. Cell Metab. 2018;28:817–832.e8. doi: 10.1016/j.cmet.2018.09.001. PubMed DOI PMC

Ding M., Van der Kwast T.H., Vellanki R.N., Foltz W.D., McKee T.D., Sonenberg N., Pandolfi P.P., Koritzinsky M., Wouters B.G. The mTOR Targets 4E-BP1/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-driven Prostate Cancer. Mol. Cancer Res. 2018;16:682–695. doi: 10.1158/1541-7786.MCR-17-0696. PubMed DOI

Wagner C.A., Roque P.J., Mileur T.R., Liggitt D., Goverman J.M. Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity. J. Clin. Investig. 2020;130:203–213. doi: 10.1172/JCI132531. PubMed DOI PMC

Yuen M., Ottenheijm C.A.C. Nebulin: Big protein with big responsibilities. J. Muscle Res. Cell Motil. 2020;41:103–124. doi: 10.1007/s10974-019-09565-3. PubMed DOI PMC

Zanconato F., Cordenonsi M., Piccolo S. YAP/TAZ at the Roots of Cancer. Cancer Cell. 2016;29:783–803. doi: 10.1016/j.ccell.2016.05.005. PubMed DOI PMC

Chatzifrangkeskou M., O’Neill E. When Hippo meets actin in the nucleus. Mol. Cell. Oncol. 2019;6:e1638728. doi: 10.1080/23723556.2019.1638728. PubMed DOI PMC

Imai Y., Maru Y., Tanaka J. Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies. Cancer Sci. 2016;107:1543–1549. doi: 10.1111/cas.13062. PubMed DOI PMC

Skultetyova L., Ustinova K., Kutil Z., Novakova Z., Pavlicek J., Mikesova J., Trapl D., Baranova P., Havlinova B., Hubalek M., et al. Human histone deacetylase 6 shows strong preference for tubulin dimers over assembled microtubules. Sci. Rep. 2017;7:11547. doi: 10.1038/s41598-017-11739-3. PubMed DOI PMC

He M., Zhou Z., Shah A.A., Hong Y., Chen Q., Wan Y. New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics. Cell Div. 2016;11:4. doi: 10.1186/s13008-016-0013-6. PubMed DOI PMC

Arkun Y., Yasemi M. Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations. PLoS ONE. 2018;13:e0195513. doi: 10.1371/journal.pone.0195513. PubMed DOI PMC

Li Y., Corradetti M.N., Inoki K., Guan K.L. TSC2: Filling the GAP in the mTOR signaling pathway. Trends Biochem. Sci. 2004;29:32–38. doi: 10.1016/j.tibs.2003.11.007. PubMed DOI

Salmond R.J., Emery J., Okkenhaug K., Zamoyska R. MAPK, phosphatidylinositol 3-kinase, and mammalian target of rapamycin pathways converge at the level of ribosomal protein S6 phosphorylation to control metabolic signaling in CD8 T cells. J. Immunol. 2009;183:7388–7397. doi: 10.4049/jimmunol.0902294. PubMed DOI

Wang J., Whiteman M.W., Lian H., Wang G., Singh A., Huang D., Denmark T. A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1. J. Biol. Chem. 2009;284:21412–21424. doi: 10.1074/jbc.M109.026013. PubMed DOI PMC

Roux P.P., Ballif B.A., Anjum R., Gygi S.P., Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA. 2004;101:13489–13494. doi: 10.1073/pnas.0405659101. PubMed DOI PMC

Novakova J., Talacko P., Novak P., Valis K. The MEK-ERK-MST1 Axis Potentiates the Activation of the Extrinsic Apoptotic Pathway during GDC-0941 Treatment in Jurkat T Cells. Cells. 2019;8:191. doi: 10.3390/cells8020191. PubMed DOI PMC

Ding Q., Xia W., Liu J.C., Yang J.Y., Lee D.F., Xia J., Bartholomeusz G., Li Y., Pan Y., Li Z., et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol. Cell. 2005;19:159–170. doi: 10.1016/j.molcel.2005.06.009. PubMed DOI

De Mesquita D.D., Zhan Q., Crossley L., Badwey J.A. p90-RSK and Akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. FEBS Lett. 2001;502:84–88. doi: 10.1016/S0014-5793(01)02669-2. PubMed DOI

Hornbeck P.V., Chabra I., Kornhauser J.M., Skrzypek E., Zhang B. PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation. Proteomics. 2004;4:1551–1561. doi: 10.1002/pmic.200300772. PubMed DOI

Tsuiko O., Jatsenko T., Parameswaran Grace L.K., Kurg A., Vermeesch J.R., Lanner F., Altmae S., Salumets A. A speculative outlook on embryonic aneuploidy: Can molecular pathways be involved? Dev. Biol. 2019;447:3–13. doi: 10.1016/j.ydbio.2018.01.014. PubMed DOI

Azad T., Janse van Rensburg H.J., Lightbody E.D., Neveu B., Champagne A., Ghaffari A., Kay V.R., Hao Y., Shen H., Yeung B., et al. A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis. Nat. Commun. 2018;9:1061. doi: 10.1038/s41467-018-03278-w. PubMed DOI PMC

Sheridan C., Brumatti G., Elgendy M., Brunet M., Martin S.J. An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene. 2010;29:6428–6441. doi: 10.1038/onc.2010.380. PubMed DOI

Elgendy M., Sheridan C., Brumatti G., Martin S.J. Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol. Cell. 2011;42:23–35. doi: 10.1016/j.molcel.2011.02.009. PubMed DOI

Tomiyama A., Tachibana K., Suzuki K., Seino S., Sunayama J., Matsuda K.I., Sato A., Matsumoto Y., Nomiya T., Nemoto K., et al. MEK-ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death. Cell Death Dis. 2010;1:e60. doi: 10.1038/cddis.2010.37. PubMed DOI PMC

Xue H., Liu L., Zhao Z., Zhang Z., Guan Y., Cheng H., Zhou Y., Tai G. The N-terminal tail coordinates with carbohydrate recognition domain to mediate galectin-3 induced apoptosis in T cells. Oncotarget. 2017;8:49824–49838. doi: 10.18632/oncotarget.17760. PubMed DOI PMC

Zong D., Li J., Cai S., He S., Liu Q., Jiang J., Chen S., Long Y., Chen Y., Chen P., et al. Notch1 regulates endothelial apoptosis via the ERK pathway in chronic obstructive pulmonary disease. Am. J. Physiol. Cell Physiol. 2018;315:C330–C340. doi: 10.1152/ajpcell.00182.2017. PubMed DOI PMC

Satoh R., Hagihara K., Matsuura K., Manse Y., Kita A., Kunoh T., Masuko T., Moriyama M., Moriyama H., Tanabe G., et al. Identification of ACA-28, a 1′-acetoxychavicol acetate analogue compound, as a novel modulator of ERK MAPK signaling, which preferentially kills human melanoma cells. Genes Cells. 2017;22:608–618. doi: 10.1111/gtc.12499. PubMed DOI

Das Gupta S., Halder B., Gomes A., Gomes A. Bengalin initiates autophagic cell death through ERK-MAPK pathway following suppression of apoptosis in human leukemic U937 cells. Life Sci. 2013;93:271–276. doi: 10.1016/j.lfs.2013.06.022. PubMed DOI

Pathania A.S., Kumar S., Guru S.K., Bhushan S., Sharma P.R., Aithagani S.K., Singh P.P., Vishwakarma R.A., Kumar A., Malik F. The synthetic tryptanthrin analogue suppresses STAT3 signaling and induces caspase dependent apoptosis via ERK up regulation in human leukemia HL-60 cells. PLoS ONE. 2014;9:e110411. doi: 10.1371/journal.pone.0110411. PubMed DOI PMC

Zhang B., Hirahashi J., Cullere X., Mayadas T.N. Elucidation of molecular events leading to neutrophil apoptosis following phagocytosis: Cross-talk between caspase 8, reactive oxygen species, and MAPK/ERK activation. J. Biol. Chem. 2003;278:28443–28454. doi: 10.1074/jbc.M210727200. PubMed DOI

Cagnol S., Van Obberghen-Schilling E., Chambard J.C. Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death. Apoptosis. 2006;11:337–346. doi: 10.1007/s10495-006-4065-y. PubMed DOI

Finlay D., Howes A., Vuori K. Critical role for caspase-8 in epidermal growth factor signaling. Cancer Res. 2009;69:5023–5029. doi: 10.1158/0008-5472.CAN-08-3731. PubMed DOI PMC

Zhang G., He J., Ye X., Zhu J., Hu X., Shen M., Ma Y., Mao Z., Song H., Chen F. beta-Thujaplicin induces autophagic cell death, apoptosis, and cell cycle arrest through ROS-mediated Akt and p38/ERK MAPK signaling in human hepatocellular carcinoma. Cell Death Dis. 2019;10:255. doi: 10.1038/s41419-019-1492-6. PubMed DOI PMC

Nguyen T.T., Tran E., Nguyen T.H., Do P.T., Huynh T.H., Huynh H. The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis. 2004;25:647–659. doi: 10.1093/carcin/bgh052. PubMed DOI

Unni A.M., Harbourne B., Oh M.H., Wild S., Ferrarone J.R., Lockwood W.W., Varmus H. Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells. Elife. 2018;7:e33718. doi: 10.7554/eLife.33718. PubMed DOI PMC

Wu P.K., Hong S.K., Yoon S.H., Park J.I. Active ERK2 is sufficient to mediate growth arrest and differentiation signaling. FEBS J. 2015;282:1017–1030. doi: 10.1111/febs.13197. PubMed DOI PMC

Huang K., Chen Y., Zhang R., Wu Y., Ma Y., Fang X., Shen S. Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis. 2018;9:157. doi: 10.1038/s41419-017-0166-5. PubMed DOI PMC

Zhang P., Zheng Z., Ling L., Yang X., Zhang N., Wang X., Hu M., Xia Y., Ma Y., Yang H., et al. w09, a novel autophagy enhancer, induces autophagy-dependent cell apoptosis via activation of the EGFR-mediated RAS-RAF1-MAP2K-MAPK1/3 pathway. Autophagy. 2017;13:1093–1112. doi: 10.1080/15548627.2017.1319039. PubMed DOI PMC

Liu E., Li J., Shi S., Wang X., Liang T., Wu B., Li Q. Sustained ERK activation-mediated proliferation inhibition of farrerol on human gastric carcinoma cell line by G0/G1-phase cell-cycle arrest. Eur. J. Cancer Prev. 2016;25:490–499. doi: 10.1097/CEJ.0000000000000212. PubMed DOI

Deschenes-Simard X., Gaumont-Leclerc M.F., Bourdeau V., Lessard F., Moiseeva O., Forest V., Igelmann S., Mallette F.A., Saba-El-Leil M.K., Meloche S., et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev. 2013;27:900–915. doi: 10.1101/gad.203984.112. PubMed DOI PMC

Ohtsuka S., Ogawa S., Wakamatsu E., Abe R. Cell cycle arrest caused by MEK/ERK signaling is a mechanism for suppressing growth of antigen-hyperstimulated effector T cells. Int. Immunol. 2016;28:547–557. doi: 10.1093/intimm/dxw037. PubMed DOI PMC

Ohm A.M., Affandi T., Reyland M.E. EGF receptor and PKCdelta kinase activate DNA damage-induced pro-survival and pro-apoptotic signaling via biphasic activation of ERK and MSK1 kinases. J. Biol. Chem. 2019;294:4488–4497. doi: 10.1074/jbc.RA118.006944. PubMed DOI PMC

Harvey K.F., Zhang X., Thomas D.M. The Hippo pathway and human cancer. Nat. Rev. Cancer. 2013;13:246–257. doi: 10.1038/nrc3458. PubMed DOI

Zhou D., Conrad C., Xia F., Park J.S., Payer B., Yin Y., Lauwers G.Y., Thasler W., Lee J.T., Avruch J., et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16:425–438. doi: 10.1016/j.ccr.2009.09.026. PubMed DOI PMC

Valis K., Talacko P., Grobarova V., Cerny J., Novak P. Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis. Exp. Cell Res. 2016;349:273–281. doi: 10.1016/j.yexcr.2016.10.018. PubMed DOI

Zanconato F., Forcato M., Battilana G., Azzolin L., Quaranta E., Bodega B., Rosato A., Bicciato S., Cordenonsi M., Piccolo S. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 2015;17:1218–1227. doi: 10.1038/ncb3216. PubMed DOI PMC

Lin C., Xu X. YAP1-TEAD1-Glut1 axis dictates the oncogenic phenotypes of breast cancer cells by modulating glycolysis. Biomed. Pharmacother. 2017;95:789–794. doi: 10.1016/j.biopha.2017.08.091. PubMed DOI

Wang L., Sun J., Gao P., Su K., Wu H., Li J., Lou W. Wnt1-inducible signaling protein 1 regulates laryngeal squamous cell carcinoma glycolysis and chemoresistance via the YAP1/TEAD1/GLUT1 pathway. J. Cell. Physiol. 2019;234:15941–15950. doi: 10.1002/jcp.28253. PubMed DOI

Valis K., Prochazka L., Boura E., Chladova J., Obsil T., Rohlena J., Truksa J., Dong L.F., Ralph S.J., Neuzil J. Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res. 2011;71:946–954. doi: 10.1158/0008-5472.CAN-10-2203. PubMed DOI

Obexer P., Geiger K., Ambros P.F., Meister B., Ausserlechner M.J. FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell Death Differ. 2007;14:534–547. doi: 10.1038/sj.cdd.4402017. PubMed DOI

Slavata L., Chmelik J., Kavan D., Filandrova R., Fiala J., Rosulek M., Mrazek H., Kukacka Z., Valis K., Man P., et al. MS-Based Approaches Enable the Structural Characterization of Transcription Factor/DNA Response Element Complex. Biomolecules. 2019;9:535. doi: 10.3390/biom9100535. PubMed DOI PMC

Ardestani A., Paroni F., Azizi Z., Kaur S., Khobragade V., Yuan T., Frogne T., Tao W., Oberholzer J., Pattou F., et al. MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nat. Med. 2014;20:385–397. doi: 10.1038/nm.3482. PubMed DOI PMC

Smoot R.L., Werneburg N.W., Sugihara T., Hernandez M.C., Yang L., Mehner C., Graham R.P., Bronk S.F., Truty M.J., Gores G.J. Platelet-derived growth factor regulates YAP transcriptional activity via Src family kinase dependent tyrosine phosphorylation. J. Cell. Biochem. 2018;119:824–836. doi: 10.1002/jcb.26246. PubMed DOI PMC

Del Re D.P., Matsuda T., Zhai P., Maejima Y., Jain M.R., Liu T., Li H., Hsu C.P., Sadoshima J. Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol. Cell. 2014;54:639–650. doi: 10.1016/j.molcel.2014.04.007. PubMed DOI PMC

Dong D.J., Jing Y.P., Liu W., Wang J.X., Zhao X.F. The Steroid Hormone 20-Hydroxyecdysone Up-regulates Ste-20 Family Serine/Threonine Kinase Hippo to Induce Programmed Cell Death. J. Biol. Chem. 2015;290:24738–24746. doi: 10.1074/jbc.M115.643783. PubMed DOI PMC

Lee K.K., Ohyama T., Yajima N., Tsubuki S., Yonehara S. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J. Biol. Chem. 2001;276:19276–19285. doi: 10.1074/jbc.M005109200. PubMed DOI

De Souza P.M., Kankaanranta H., Michael A., Barnes P.J., Giembycz M.A., Lindsay M.A. Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis. Blood. 2002;99:3432–3438. doi: 10.1182/blood.V99.9.3432. PubMed DOI

Ura S., Masuyama N., Graves J.D., Gotoh Y. Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc. Natl. Acad. Sci. USA. 2001;98:10148–10153. doi: 10.1073/pnas.181161698. PubMed DOI PMC

Hao W., Takano T., Guillemette J., Papillon J., Ren G., Cybulsky A.V. Induction of apoptosis by the Ste20-like kinase SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38. J. Biol. Chem. 2006;281:3075–3084. doi: 10.1074/jbc.M511744200. PubMed DOI

Shin S.Y., Nguyen L.K. Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis. Genes. 2016;7:44. doi: 10.3390/genes7080044. PubMed DOI PMC

Collak F.K., Yagiz K., Luthringer D.J., Erkaya B., Cinar B. Threonine-120 phosphorylation regulated by phosphoinositide-3-kinase/Akt and mammalian target of rapamycin pathway signaling limits the antitumor activity of mammalian sterile 20-like kinase 1. J. Biol. Chem. 2012;287:23698–23709. doi: 10.1074/jbc.M112.358713. PubMed DOI PMC

Kim S.J., Lee J.S., Kim S.M. 3,3′-Diindolylmethane suppresses growth of human esophageal squamous cancer cells by G1 cell cycle arrest. Oncol. Rep. 2012;27:1669–1673. doi: 10.3892/or.2012.1662. PubMed DOI

Xia H., Dai X., Yu H., Zhou S., Fan Z., Wei G., Tang Q., Gong Q., Bi F. EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: The mechanism and its implications in targeted therapy. Cell Death Dis. 2018;9:269. doi: 10.1038/s41419-018-0302-x. PubMed DOI PMC

Kim N.G., Gumbiner B.M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J. Cell Biol. 2015;210:503–515. doi: 10.1083/jcb.201501025. PubMed DOI PMC

Turunen S.P., von Nandelstadh P., Ohman T., Gucciardo E., Seashore-Ludlow B., Martins B., Rantanen V., Li H., Hopfner K., Ostling P., et al. FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis. Cell Death Differ. 2019;26:2577–2593. doi: 10.1038/s41418-019-0321-x. PubMed DOI PMC

Zhang S., Song X., Cao D., Xu Z., Fan B., Che L., Hu J., Chen B., Dong M., Pilo M.G., et al. Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice. J. Hepatol. 2017;67:1194–1203. doi: 10.1016/j.jhep.2017.07.006. PubMed DOI PMC

Liang N., Zhang C., Dill P., Panasyuk G., Pion D., Koka V., Gallazzini M., Olson E.N., Lam H., Henske E.P., et al. Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J. Exp. Med. 2014;211:2249–2263. doi: 10.1084/jem.20140341. PubMed DOI PMC

Valis K., Grobarova V., Hernychova L., Buganova M., Kavan D., Kalous M., Cerny J., Stodulkova E., Kuzma M., Flieger M., et al. Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B. Oncotarget. 2017;8:103137–103153. doi: 10.18632/oncotarget.21663. PubMed DOI PMC

Fu C.Y., Chen M.C., Tseng Y.S., Chen M.C., Zhou Z., Yang J.J., Lin Y.M., Viswanadha V.P., Wang G., Huang C.Y. Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression. Environ. Toxicol. 2019;34:902–911. doi: 10.1002/tox.22761. PubMed DOI

Yu T., Ji J., Guo Y.L. MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells. Biochem. Biophys. Res. Commun. 2013;441:53–58. doi: 10.1016/j.bbrc.2013.10.008. PubMed DOI

Zhou X., Su J., Feng S., Wang L., Yin X., Yan J., Wang Z. Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells. Oncotarget. 2016;7:79076–79088. doi: 10.18632/oncotarget.12596. PubMed DOI PMC

Gersey Z.C., Rodriguez G.A., Barbarite E., Sanchez A., Walters W.M., Ohaeto K.C., Komotar R.J., Graham R.M. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species. BMC Cancer. 2017;17:99. doi: 10.1186/s12885-017-3058-2. PubMed DOI PMC

Sengupta S., Nagalingam A., Muniraj N., Bonner M.Y., Mistriotis P., Afthinos A., Kuppusamy P., Lanoue D., Cho S., Korangath P., et al. Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. Oncogene. 2017;36:5709–5721. doi: 10.1038/onc.2017.164. PubMed DOI PMC

Mohseni M., Sun J., Lau A., Curtis S., Goldsmith J., Fox V.L., Wei C., Frazier M., Samson O., Wong K.K., et al. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat. Cell Biol. 2014;16:108–117. doi: 10.1038/ncb2884. PubMed DOI PMC

Tanaka K., Osada H., Murakami-Tonami Y., Horio Y., Hida T., Sekido Y. Statin suppresses Hippo pathway-inactivated malignant mesothelioma cells and blocks the YAP/CD44 growth stimulatory axis. Cancer Lett. 2017;385:215–224. doi: 10.1016/j.canlet.2016.10.020. PubMed DOI

Li J., Wang H., Wang L., Tan R., Zhu M., Zhong X., Zhang Y., Chen B., Wang L. Decursin inhibits the growth of HepG2 hepatocellular carcinoma cells via Hippo/YAP signaling pathway. Phytother. Res. 2018;32:2456–2465. doi: 10.1002/ptr.6184. PubMed DOI

Chai Y., Xiang K., Wu Y., Zhang T., Liu Y., Liu X., Zhen W., Si Y. Cucurbitacin B Inhibits the Hippo-YAP Signaling Pathway and Exerts Anticancer Activity in Colorectal Cancer Cells. Med. Sci. Monit. 2018;24:9251–9258. doi: 10.12659/MSM.911594. PubMed DOI PMC

Li Y.W., Xu J., Zhu G.Y., Huang Z.J., Lu Y., Li X.Q., Wang N., Zhang F.X. Apigenin suppresses the stem cell-like properties of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Cell Death Discov. 2018;4:105. doi: 10.1038/s41420-018-0124-8. PubMed DOI PMC

Fritsche-Guenther R., Witzel F., Kempa S., Brummer T., Sers C., Bluthgen N. Effects of RAF inhibitors on PI3K/AKT signalling depend on mutational status of the RAS/RAF signalling axis. Oncotarget. 2016;7:7960–7969. doi: 10.18632/oncotarget.6959. PubMed DOI PMC

Manning B.D., Toker A. AKT/PKB Signaling: Navigating the Network. Cell. 2017;169:381–405. doi: 10.1016/j.cell.2017.04.001. PubMed DOI PMC

Zhou J., Du T., Li B., Rong Y., Verkhratsky A., Peng L. Crosstalk Between MAPK/ERK and PI3K/AKT Signal Pathways During Brain Ischemia/Reperfusion. ASN Neuro. 2015;7:1759091415602463. doi: 10.1177/1759091415602463. PubMed DOI PMC

Rheault T.R., Stellwagen J.C., Adjabeng G.M., Hornberger K.R., Petrov K.G., Waterson A.G., Dickerson S.H., Mook R.A., Jr., Laquerre S.G., King A.J., et al. Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. ACS Med. Chem. Lett. 2013;4:358–362. doi: 10.1021/ml4000063. PubMed DOI PMC

Henry J.R., Kaufman M.D., Peng S.B., Ahn Y.M., Caldwell T.M., Vogeti L., Telikepalli H., Lu W.P., Hood M.M., Rutkoski T.J., et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. J. Med. Chem. 2015;58:4165–4179. doi: 10.1021/acs.jmedchem.5b00067. PubMed DOI

Ahronian L.G., Sennott E.M., Van Allen E.M., Wagle N., Kwak E.L., Faris J.E., Godfrey J.T., Nishimura K., Lynch K.D., Mermel C.H., et al. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. Cancer Discov. 2015;5:358–367. doi: 10.1158/2159-8290.CD-14-1518. PubMed DOI PMC

Yaeger R., Corcoran R.B. Targeting Alterations in the RAF-MEK Pathway. Cancer Discov. 2019;9:329–341. doi: 10.1158/2159-8290.CD-18-1321. PubMed DOI PMC

Liu F., Yang X., Geng M., Huang M. Targeting ERK, an Achilles’ Heel of the MAPK pathway, in cancer therapy. Acta Pharm. Sin. B. 2018;8:552–562. doi: 10.1016/j.apsb.2018.01.008. PubMed DOI PMC

Feng R., Gong J., Wu L., Wang L., Zhang B., Liang G., Zheng H., Xiao H. MAPK and Hippo signaling pathways crosstalk via the RAF-1/MST-2 interaction in malignant melanoma. Oncol. Rep. 2017;38:1199–1205. doi: 10.3892/or.2017.5774. PubMed DOI

Fan R., Kim N.G., Gumbiner B.M. Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc. Natl. Acad. Sci. USA. 2013;110:2569–2574. doi: 10.1073/pnas.1216462110. PubMed DOI PMC

Azad T., Nouri K., Janse van Rensburg H.J., Maritan S.M., Wu L., Hao Y., Montminy T., Yu J., Khanal P., Mulligan L.M., et al. A gain-of-functional screen identifies the Hippo pathway as a central mediator of receptor tyrosine kinases during tumorigenesis. Oncogene. 2020;39:334–355. doi: 10.1038/s41388-019-0988-y. PubMed DOI

Coggins G.E., Farrel A., Rathi K.S., Hayes C.M., Scolaro L., Rokita J.L., Maris J.M. YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling. Cancer Res. 2019;79:6204–6214. doi: 10.1158/0008-5472.CAN-19-1415. PubMed DOI PMC

Li H., Li Q., Dang K., Ma S., Cotton J.L., Yang S., Zhu L.J., Deng A.C., Ip Y.T., Johnson R.L., et al. YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression. Cell Rep. 2019;29:3200–3211.e4. doi: 10.1016/j.celrep.2019.03.021. PubMed DOI PMC

Hu C., Yang J., Su H.Y., Waldron R.T., Zhi M., Li L., Xia Q., Pandol S.J., Lugea A. Yes-Associated Protein 1 Plays Major Roles in Pancreatic Stellate Cell Activation and Fibroinflammatory Responses. Front. Physiol. 2019;10:1467. doi: 10.3389/fphys.2019.01467. PubMed DOI PMC

Dang C.V. MYC on the path to cancer. Cell. 2012;149:22–35. doi: 10.1016/j.cell.2012.03.003. PubMed DOI PMC

Broecker-Preuss M., Becher-Boveleth N., Bockisch A., Duhrsen U., Muller S. Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. J. Transl. Med. 2017;15:158. doi: 10.1186/s12967-017-1258-9. PubMed DOI PMC

Liu Y., Zhang Z., Song T., Liang F., Xie M., Sheng H. Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl-2 through ERK1/2. Br. J. Pharmacol. 2013;169:1612–1623. doi: 10.1111/bph.12243. PubMed DOI PMC

Mukherjee N., Strosnider A., Vagher B., Lambert K.A., Slaven S., Robinson W.A., Amato C.M., Couts K.L., Bemis J.G.T., Turner J.A., et al. BH3 mimetics induce apoptosis independent of DRP-1 in melanoma. Cell Death Dis. 2018;9:907. doi: 10.1038/s41419-018-0932-z. PubMed DOI PMC

Verhaegen M., Bauer J.A., Martin de la Vega C., Wang G., Wolter K.G., Brenner J.C., Nikolovska-Coleska Z., Bengtson A., Nair R., Elder J.T., et al. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Cancer Res. 2006;66:11348–11359. doi: 10.1158/0008-5472.CAN-06-1748. PubMed DOI

Benvenuto M., Mattera R., Sticca J.I., Rossi P., Cipriani C., Giganti M.G., Volpi A., Modesti A., Masuelli L., Bei R. Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma. Front. Pharmacol. 2018;9:1269. doi: 10.3389/fphar.2018.01269. PubMed DOI PMC

Wang J., Sun P., Chen Y., Yao H., Wang S. Novel 2-phenyloxypyrimidine derivative induces apoptosis and autophagy via inhibiting PI3K pathway and activating MAPK/ERK signaling in hepatocellular carcinoma cells. Sci. Rep. 2018;8:10923. doi: 10.1038/s41598-018-29199-8. PubMed DOI PMC

Cagnol S., Chambard J.C. ERK and cell death: Mechanisms of ERK-induced cell death—Apoptosis, autophagy and senescence. FEBS J. 2010;277:2–21. doi: 10.1111/j.1742-4658.2009.07366.x. PubMed DOI

Atiq R., Hertz R., Eldad S., Smeir E., Bar-Tana J. Suppression of B-Raf(V600E) cancers by MAPK hyper-activation. Oncotarget. 2016;7:18694–18704. doi: 10.18632/oncotarget.7909. PubMed DOI PMC

Yu S., Zhang M., Huang L., Ma Z., Gong X., Liu W., Zhang J., Chen L., Yu Z., Zhao W., et al. ERK1 indicates good prognosis and inhibits breast cancer progression by suppressing YAP1 signaling. Aging. 2019;11:12295–12314. doi: 10.18632/aging.102572. PubMed DOI PMC

Nieuwenhuis S., Okkersen K., Widomska J., Blom P., t Hoen P.A.C., van Engelen B., Glennon J.C. Insulin Signaling as a Key Moderator in Myotonic Dystrophy Type 1. Front. Neurol. 2019;10:1229. doi: 10.3389/fneur.2019.01229. PubMed DOI PMC