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Current Drug Targets

Author(s): Aarti Tiwari, Saloni Rahi and Sidharth Mehan*

DOI: 10.2174/1389450121666201020155010

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Elucidation of Abnormal Extracellular Regulated Kinase (ERK) Signaling and Associations with Syndromic and Non-syndromic Autism

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Abstract

Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chromosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized primarily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has recently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addition, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder.

Keywords: Autism spectrum disorder (ASD), ERK pathway, RASopathy, Syndromic autism, non-syndromic autism, chromosome anomalies.

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[1]
Karande S. Autism: A review for family physicians. Indian J Med Sci 2006; 60(5): 205-15.
[http://dx.doi.org/10.4103/0019-5359.25683] [PMID: 16733293]
[2]
Beebe B, Sloate P. Assesment and treatment of difficulties in mother‐infant attunement in the first three years of life: A case history. Psychoanal Inq 1982; 1(4): 601-23.
[http://dx.doi.org/10.1080/07351698209533422]
[3]
Magallón-Neri E, Vila D, Santiago K, García P, Canino G. The prevalence of psychiatric disorders and mental health services utilization by parents and relatives living with individuals with autism spectrum disorders in puertorico. J Nerv Ment Dis 2018; 206(4): 226-30.
[PMID: 29112530]
[4]
Berry K, Russell K, Frost K. Restricted and repetitive behaviors in autism spectrum disorder: A review of associated features and presentation across clinical populations. Curr Dev Disord Rep 2018; 5(2): 108-15.
[http://dx.doi.org/10.1007/s40474-018-0139-0]
[5]
Akhondzadeh S, Tajdar H, Mohammadi MR, et al. A double-blind placebo controlled trial of piracetam added to risperidone in patients with autistic disorder. Child Psychiatry Hum Dev 2008; 39(3): 237-45.
[http://dx.doi.org/10.1007/s10578-007-0084-3] [PMID: 17929164]
[6]
Aman MG, Lam KS, Collier-Crespin A. Prevalence and patterns of use of psychoactive medicines among individuals with autism in the Autism Society of Ohio. J Autism Dev Disord 2003; 33(5): 527-34.
[http://dx.doi.org/10.1023/A:1025883612879] [PMID: 14594332]
[7]
Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol 2005; 15(6): 869-84.
[http://dx.doi.org/10.1089/cap.2005.15.869] [PMID: 16379507]
[8]
Anderson GM, Scahill L, McCracken JT, et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry 2007; 61(4): 545-50.
[http://dx.doi.org/10.1016/j.biopsych.2006.02.032] [PMID: 16730335]
[9]
Gagliano A, Germanò E, Pustorino G, et al. Risperidone treatment of children with autistic disorder: effectiveness, tolerability, and pharmacokinetic implications. J Child Adolesc Psychopharmacol 2004; 14(1): 39-47.
[http://dx.doi.org/10.1089/104454604773840472] [PMID: 15142390]
[10]
McCracken JT, McGough J, Shah B, et al. Research units on pediatric psychopharmacology autism network. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002; 347(5): 314-21.
[http://dx.doi.org/10.1056/NEJMoa013171] [PMID: 12151468]
[11]
LeClerc S, Easley D. Pharmacological therapies for autism spectrum disorder: a review. P&T 2015; 40(6): 389-97.
[PMID: 26045648]
[12]
Farmer CA, Aman MG. Aripiprazole for the treatment of irritability associated with autism. Expert Opin Pharmacother 2011; 12(4): 635-40.
[http://dx.doi.org/10.1517/14656566.2011.557661] [PMID: 21294670]
[13]
Casey AB, Canal CE. Classics in chemical neuroscience: aripiprazole. ACS Chem Neurosci 2017; 8(6): 1135-46.
[http://dx.doi.org/10.1021/acschemneuro.7b00087] [PMID: 28368577]
[14]
Erickson CA, Stigler KA, Posey DJ, McDougle CJ. Aripiprazole in autism spectrum disorders and fragile X syndrome. Neurotherapeutics 2010; 7(3): 258-63.
[http://dx.doi.org/10.1016/j.nurt.2010.04.001] [PMID: 20643378]
[15]
Blankenship K, Erickson CA, Stigler KA, Posey DJ, McDougle CJ. Aripiprazole for irritability associated with autistic disorder in children and adolescents aged 6-17 years. Ped Health 2010; 4(4): 375-81.
[http://dx.doi.org/10.2217/phe.10.45] [PMID: 21359119]
[16]
Burke SP, Stratton K, Baciu A, Eds. The future of drug safety: promoting and protecting the health of the public. National Academies Press 2007.
[17]
Miller NJ, Sampson J, Candeias LP, Bramley PM, Rice-Evans CA. Antioxidant activities of carotenes and xanthophylls. FEBS Lett 1996; 384(3): 240-2.
[http://dx.doi.org/10.1016/0014-5793(96)00323-7] [PMID: 8617362]
[18]
Gencer O, Emiroglu FN, Miral S, Baykara B, Baykara A, Dirik E. Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder. An open label maintenance study. Eur Child Adolesc Psychiatry 2008; 17(4): 217-25.
[http://dx.doi.org/10.1007/s00787-007-0656-6] [PMID: 18026891]
[19]
Moore ML, Eichner SF, Jones JR. Treating functional impairment of autism with selective serotonin-reuptake inhibitors. Ann Pharmacother 2004; 38(9): 1515-9.
[http://dx.doi.org/10.1345/aph.1D543] [PMID: 15292500]
[20]
Anagnostou E, Soorya L, Chaplin W, et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012; 3(1): 16.
[http://dx.doi.org/10.1186/2040-2392-3-16] [PMID: 23216716]
[21]
Dadds MR, MacDonald E, Cauchi A, Williams K, Levy F, Brennan J. Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord 2014; 44(3): 521-31.
[http://dx.doi.org/10.1007/s10803-013-1899-3] [PMID: 23888359]
[22]
Chez MG, Buchanan CP, Bagan BT, et al. Secretin and autism: a two-part clinical investigation. J Autism Dev Disord 2000; 30(2): 87-94.
[http://dx.doi.org/10.1023/A:1005443119324] [PMID: 10832772]
[23]
Buitelaar JK. Open-label treatment with risperidone of 26 psychiatrically-hospitalized children and adolescents with mixed diagnoses and aggressive behavior. J Child Adolesc Psychopharmacol 2000; 10(1): 19-26.
[http://dx.doi.org/10.1089/cap.2000.10.19] [PMID: 10755578]
[24]
Hirota T, Schwartz S, Correll CU. Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. J Am Acad Child Adolesc Psychiatry 2014; 53(2): 153-73.
[http://dx.doi.org/10.1016/j.jaac.2013.11.009] [PMID: 24472251]
[25]
Carminati GG, Deriaz N, Bertschy G. Low-dose venlafaxine in three adolescents and young adults with autistic disorder improves self-injurious behavior and attention deficit/hyperactivity disorders (ADHD)-like symptoms. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30(2): 312-5.
[http://dx.doi.org/10.1016/j.pnpbp.2005.10.002] [PMID: 16307837]
[26]
Carminati GG, Gerber F, Darbellay B, et al. Using venlafaxine to treat behavioral disorders in patients with autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65: 85-95.
[http://dx.doi.org/10.1016/j.pnpbp.2015.09.002] [PMID: 26361994]
[27]
Posey DJ, McDougle CJ. Pharmacotherapeutic management of autism. Expert Opin Pharmacother 2001; 2(4): 587-600.
[http://dx.doi.org/10.1517/14656566.2.4.587] [PMID: 11336609]
[28]
Armenteros JL, Lewis JE. Citalopram treatment for impulsive aggression in children and adolescents: an open pilot study. J Am Acad Child Adolesc Psychiatry 2002; 41(5): 522-9.
[http://dx.doi.org/10.1097/00004583-200205000-00009] [PMID: 12014784]
[29]
Zarate CA, Manji HK. Putative drugs and targets for bipolar disorder. Mt Sinai J Med 2008; 75(3): 226.
[http://dx.doi.org/10.1002/msj.20042] [PMID: 18704977]
[30]
Posey DJ, Guenin KD, Kohn AE, Swiezy NB, McDougle CJ. A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders. J Child Adolesc Psychopharmacol 2001; 11(3): 267-77.
[http://dx.doi.org/10.1089/10445460152595586] [PMID: 11642476]
[31]
Basselin M, Nguyen HN, Chang L, Bell JM, Rapoport SI. Acute but not chronic donepezil administration increases muscarinic receptor-mediated brain signaling involving arachidonic acid in unanesthetized rats. J Alzheimers Dis 2009; 17(2): 369.
[http://dx.doi.org/10.3233/JAD-2009-1058] [PMID: 19363262]
[32]
Buckley AW, Sassower K, Rodriguez AJ, et al. An open label trial of donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders. J Child Adolesc Psychopharmacol 2011; 21(4): 353-7.
[http://dx.doi.org/10.1089/cap.2010.0121] [PMID: 21851192]
[33]
Handen BL, Johnson CR, McAuliffe-Bellin SJ, Hardan AY. Safety and efficacy of Donepezil in children and adolescents with autism: Behavioral measures. Int Public Health J 2010; 2: 125-34.
[34]
Rao LG, Guns E, Rao AV. Lycopene: its role in human health and disease. Agro Food 2003; 7: 25-30.
[35]
Petyaev IM. Lycopene deficiency in ageing and cardiovascular disease. Oxidative medicine and cellular longevity 2016.
[http://dx.doi.org/10.1155/2016/3218605]
[36]
Devaraj S, Mathur S, Basu A, et al. A dose-response study on the effects of purified lycopene supplementation on biomarkers of oxidative stress. J Am Coll Nutr 2008; 27(2): 267-73.
[http://dx.doi.org/10.1080/07315724.2008.10719699] [PMID: 18689558]
[37]
Werling DM, Geschwind DH. Sex differences in autism spectrum disorders. Curr Opin Neurol 2013; 26(2): 146-53.
[http://dx.doi.org/10.1097/WCO.0b013e32835ee548] [PMID: 23406909]
[38]
Li Q, Zhou JM. The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience 2016; 324: 131-9.
[http://dx.doi.org/10.1016/j.neuroscience.2016.03.013] [PMID: 26964681]
[39]
Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry 2002; 7(2)(Suppl. 2): S42-3.
[http://dx.doi.org/10.1038/sj.mp.4001177] [PMID: 12142947]
[40]
Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology 2006; 13(3): 171-81.
[http://dx.doi.org/10.1016/j.pathophys.2006.05.007] [PMID: 16766163]
[41]
Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 2011; 1380: 42-77.
[http://dx.doi.org/10.1016/j.brainres.2010.11.078] [PMID: 21129364]
[42]
Iossifov I, Ronemus M, Levy D, et al. De novo gene disruptions in children on the autistic spectrum. Neuron 2012; 74(2): 285-99.
[http://dx.doi.org/10.1016/j.neuron.2012.04.009] [PMID: 22542183]
[43]
Sparks BF, Friedman SD, Shaw DW, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 2002; 59(2): 184-92.
[http://dx.doi.org/10.1212/WNL.59.2.184] [PMID: 12136055]
[44]
Zhu X, Castellani RJ, Takeda A, et al. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev 2001; 123(1): 39-46.
[http://dx.doi.org/10.1016/S0047-6374(01)00342-6] [PMID: 11640950]
[45]
Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007; 26(22): 3291-310.
[http://dx.doi.org/10.1038/sj.onc.1210422] [PMID: 17496923]
[46]
Shioda N, Han F, Fukunaga K. Role of Akt and ERK signaling in the neurogenesis following brain ischemia. Int Rev Neurobiol 2009; 85: 375-87.
[http://dx.doi.org/10.1016/S0074-7742(09)85026-5] [PMID: 19607982]
[47]
Alam R, Gorska MM. Mitogen-activated protein kinase signalling and ERK1/2 bistability in asthma. Clin Exp Allergy 2011; 41(2): 149-59.
[http://dx.doi.org/10.1111/j.1365-2222.2010.03658.x] [PMID: 21121982]
[48]
Samuels IS, Saitta SC, Landreth GE. MAP’ing CNS development and cognition: an ERKsome process. Neuron 2009; 61(2): 160-7.
[http://dx.doi.org/10.1016/j.neuron.2009.01.001] [PMID: 19186160]
[49]
Anney RJ, Kenny EM, O’Dushlaine C, et al. Autism Genome Project. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders. Eur J Hum Genet 2011; 19(10): 1082-9.
[http://dx.doi.org/10.1038/ejhg.2011.75] [PMID: 21522181]
[50]
Pinto D, Pagnamenta AT, Klei L, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466(7304): 368-72.
[http://dx.doi.org/10.1038/nature09146] [PMID: 20531469]
[51]
Weiss LA, Shen Y, Korn JM, et al. Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358(7): 667-75.
[http://dx.doi.org/10.1056/NEJMoa075974] [PMID: 18184952]
[52]
Kumar RA, KaraMohamed S, Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008; 17(4): 628-38.
[http://dx.doi.org/10.1093/hmg/ddm376] [PMID: 18156158]
[53]
Wang X, Snape M, Klann E, et al. Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile x-syndrome. J Neurochem 2012; 121(4): 672-9.
[http://dx.doi.org/10.1111/j.1471-4159.2012.07722.x] [PMID: 22393900]
[54]
Chévere-Torres I, Kaphzan H, Bhattacharya A, et al. Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ΔRG mouse model of tuberous sclerosis complex. Neurobiol Dis 2012; 45(3): 1101-10.
[http://dx.doi.org/10.1016/j.nbd.2011.12.028] [PMID: 22198573]
[55]
Mi R, Ma J, Zhang D, Li L, Zhang H. Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model. J Genet Genomics 2009; 36(6): 355-61.
[http://dx.doi.org/10.1016/S1673-8527(08)60124-1] [PMID: 19539245]
[56]
Satoh Y, Endo S, Nakata T, et al. ERK2 contributes to the control of social behaviors in mice. J Neurosci 2011; 31(33): 11953-67.
[http://dx.doi.org/10.1523/JNEUROSCI.2349-11.2011] [PMID: 21849556]
[57]
Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 1999; 79(1): 143-80.
[http://dx.doi.org/10.1152/physrev.1999.79.1.143] [PMID: 9922370]
[58]
Cooper JA, Bowen-Pope DF, Raines E, Ross R, Hunter T. Similar effects of platelet-derived growth factor and epidermal growth factor on the phosphorylation of tyrosine in cellular proteins. Cell 1982; 31(1): 263-73.
[http://dx.doi.org/10.1016/0092-8674(82)90426-3] [PMID: 6186382]
[59]
Kazlauskas A, Cooper JA. Protein kinase C mediates platelet-derived growth factor-induced tyrosine phosphorylation of p42. J Cell Biol 1988; 106(4): 1395-402.
[http://dx.doi.org/10.1083/jcb.106.4.1395] [PMID: 2452172]
[60]
Ray LB, Sturgill TW. Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc Natl Acad Sci USA 1988; 85(11): 3753-7.
[http://dx.doi.org/10.1073/pnas.85.11.3753] [PMID: 3287375]
[61]
Boulton TG, Nye SH, Robbins DJ, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 1991; 65(4): 663-75.
[http://dx.doi.org/10.1016/0092-8674(91)90098-J] [PMID: 2032290]
[62]
Boulton TG, Yancopoulos GD, Gregory JS, et al. An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 1990; 249(4964): 64-7.
[http://dx.doi.org/10.1126/science.2164259] [PMID: 2164259]
[63]
Shaul YD, Seger R. ERK1c regulates Golgi fragmentation during mitosis. J Cell Biol 2006; 172(6): 885-97.
[http://dx.doi.org/10.1083/jcb.200509063] [PMID: 16533948]
[64]
Yung Y, Yao Z, Hanoch T, Seger R. ERK1b, a 46-kDa ERK isoform that is differentially regulated by MEK. J Biol Chem 2000; 275(21): 15799-808.
[http://dx.doi.org/10.1074/jbc.M910060199] [PMID: 10748187]
[65]
Gonzalez FA, Raden DL, Rigby MR, Davis RJ. Heterogeneous expression of four MAP kinase isoforms in human tissues. FEBS Lett 1992; 304(2-3): 170-8.
[http://dx.doi.org/10.1016/0014-5793(92)80612-K] [PMID: 1319925]
[66]
Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene 2007; 26(22): 3100-12.
[http://dx.doi.org/10.1038/sj.onc.1210392] [PMID: 17496909]
[67]
Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Molecular Cell Research 2007; 1773(8): 1213-26.
[PMID: 17112607]
[68]
Chen RH, Sarnecki C, Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol 1992; 12(3): 915-27.
[http://dx.doi.org/10.1128/MCB.12.3.915] [PMID: 1545823]
[69]
Lenormand P, Sardet C, Pagès G, L’Allemain G, Brunet A, Pouysségur J. Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol 1993; 122(5): 1079-88.
[http://dx.doi.org/10.1083/jcb.122.5.1079] [PMID: 8394845]
[70]
Pouysségur J, Volmat V, Lenormand P. Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Biochem Pharmacol 2002; 64(5-6): 755-63.
[http://dx.doi.org/10.1016/S0006-2952(02)01135-8] [PMID: 12213567]
[71]
Zehorai E, Yao Z, Plotnikov A, Seger R. The subcellular localization of MEK and ERK--a novel nuclear translocation signal (NTS) paves a way to the nucleus. Mol Cell Endocrinol 2010; 314(2): 213-20.
[http://dx.doi.org/10.1016/j.mce.2009.04.008] [PMID: 19406201]
[72]
Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 2006; 24(1): 21-44.
[http://dx.doi.org/10.1080/02699050500284218] [PMID: 16393692]
[73]
Meloche S, Pouysségur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 2007; 26(22): 3227-39.
[http://dx.doi.org/10.1038/sj.onc.1210414] [PMID: 17496918]
[74]
Sun J, Nan G. The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: A potential therapeutic target (Review). Int J Mol Med 2017; 39(6): 1338-46.
[http://dx.doi.org/10.3892/ijmm.2017.2962] [PMID: 28440493]
[75]
Hamdan FF, Daoud H, Piton A, et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry 2011; 69(9): 898-901.
[http://dx.doi.org/10.1016/j.biopsych.2010.11.015] [PMID: 21237447]
[76]
Kelleher RJ III, Geigenmüller U, Hovhannisyan H, et al. High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS One 2012; 7(4): e35003.
[http://dx.doi.org/10.1371/journal.pone.0035003] [PMID: 22558107]
[77]
Komiyama NH, Watabe AM, Carlisle HJ, et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci 2002; 22(22): 9721-32.
[http://dx.doi.org/10.1523/JNEUROSCI.22-22-09721.2002] [PMID: 12427827]
[78]
Herbert M, Sage C. Autism and EMF? Plausibility of a pathophysiological link - Part I. Pathophysiology 2013; 20(3): 191-209.
[79]
Blizinsky KD. Macroscopic and Microscopic Gray Matter Aberrations in Schizophrenia: Temporal Dynamics, Cognitive Correlates, and Genetic Agency (Doctoral dissertation, Northwestern University)
[80]
Osterweil EK, Krueger DD, Reinhold K, Bear MF. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J Neurosci 2010; 30(46): 15616-27.
[http://dx.doi.org/10.1523/JNEUROSCI.3888-10.2010] [PMID: 21084617]
[81]
Osterweil EK, Chuang SC, Chubykin AA, et al. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 2013; 77(2): 243-50.
[http://dx.doi.org/10.1016/j.neuron.2012.01.034] [PMID: 23352161]
[82]
Kaufmann WE, Cortell R, Kau AS, et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A 2004; 129A(3): 225-34.
[http://dx.doi.org/10.1002/ajmg.a.30229] [PMID: 15326621]
[83]
Thurman AJ, McDuffie A, Hagerman R, Abbeduto L. Psychiatric symptoms in boys with fragile X syndrome: a comparison with nonsyndromic autism spectrum disorder. Res Dev Disabil 2014; 35(5): 1072-86.
[http://dx.doi.org/10.1016/j.ridd.2014.01.032] [PMID: 24629733]
[84]
Santos AR, Kanellopoulos AK, Bagni C. Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us. Learn Mem 2014; 21(10): 543-55.
[http://dx.doi.org/10.1101/lm.035956.114] [PMID: 25227249]
[85]
Mines MA, Yuskaitis CJ, King MK, Beurel E, Jope RS. GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS One 2010; 5(3): e9706.
[http://dx.doi.org/10.1371/journal.pone.0009706] [PMID: 20300527]
[86]
Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 2012; 76(2): 325-37.
[http://dx.doi.org/10.1016/j.neuron.2012.07.022] [PMID: 23083736]
[87]
Sawicka K, Pyronneau A, Chao M, Bennett MV, Zukin RS. Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice. Proc Natl Acad Sci USA 2016; 113(41): E6290-7.
[http://dx.doi.org/10.1073/pnas.1610812113] [PMID: 27663742]
[88]
Gkogkas CG, Khoutorsky A, Cao R, et al. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep 2014; 9(5): 1742-55.
[http://dx.doi.org/10.1016/j.celrep.2014.10.064] [PMID: 25466251]
[89]
Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet 2013; 14: 355-69.
[http://dx.doi.org/10.1146/annurev-genom-091212-153523] [PMID: 23875798]
[90]
Adviento B, Corbin IL, Widjaja F, et al. Autism traits in the RASopathies. J Med Genet 2014; 51(1): 10-20.
[http://dx.doi.org/10.1136/jmedgenet-2013-101951] [PMID: 24101678]
[91]
Alfieri P, Piccini G, Caciolo C, et al. Behavioral profile in RASopathies. Am J Med Genet A 2014; 164A(4): 934-42.
[http://dx.doi.org/10.1002/ajmg.a.36374] [PMID: 24458522]
[92]
Schreiber J, Grimbergen LA, Overwater I, et al. Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models. Sci Rep 2017; 7(1): 1256.
[http://dx.doi.org/10.1038/s41598-017-01218-0] [PMID: 28455524]
[93]
Garg S, Brooks A, Burns A, et al. Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway. Dev Med Child Neurol 2017; 59(5): 544-9.
[http://dx.doi.org/10.1111/dmcn.13394] [PMID: 28160302]
[94]
Anastasaki C, Rauen KA, Patton EE. Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish. Dis Model Mech 2012; 5(4): 546-52.
[http://dx.doi.org/10.1242/dmm.008672] [PMID: 22301711]
[95]
Mendez HM, Opitz JM, Reynolds JF. Noonan syndrome: a review. Am J Med Genet 1985; 21(3): 493-506.
[http://dx.doi.org/10.1002/ajmg.1320210312] [PMID: 3895929]
[96]
Ghaziuddin M, Bolyard B, Alessi N. Autistic disorder in Noonan syndrome. J Intellect Disabil Res 1994; 38(Pt 1): 67-72.
[http://dx.doi.org/10.1111/j.1365-2788.1994.tb00349.x] [PMID: 8173225]
[97]
Paul R, Cohen DJ, Volkmar FR. Autistic behaviors in a boy with Noonan syndrome. J Autism Dev Disord 1983; 13(4): 433-4.
[http://dx.doi.org/10.1007/BF01531591] [PMID: 6662846]
[98]
Lee YS, Ehninger D, Zhou M, et al. Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome. Nat Neurosci 2014; 17(12): 1736-43.
[http://dx.doi.org/10.1038/nn.3863] [PMID: 25383899]
[99]
John AS, McDonald-McGinn DM, Zackai EH, Goldmuntz E. Aortic root dilation in patients with 22q11.2 deletion syndrome. Am J Med Genet A 2009; 149A(5): 939-42.
[http://dx.doi.org/10.1002/ajmg.a.32770] [PMID: 19353635]
[100]
Samuels IS, Karlo JC, Faruzzi AN, et al. Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function. J Neurosci 2008; 28(27): 6983-95.
[http://dx.doi.org/10.1523/JNEUROSCI.0679-08.2008] [PMID: 18596172]
[101]
Newbern J, Zhong J, Wickramasinghe RS, et al. Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development. Proc Natl Acad Sci USA 2008; 105(44): 17115-20.
[http://dx.doi.org/10.1073/pnas.0805239105] [PMID: 18952847]
[102]
Ornoy A, Weinstein-Fudim L, Ergaz Z. Genetic syndromes, maternal diseases and antenatal factors associated with autism spectrum disorders (ASD). Front Neurosci 2016; 10: 316.
[http://dx.doi.org/10.3389/fnins.2016.00316] [PMID: 27458336]
[103]
Meloni I, Bruttini M, Longo I, et al. A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet 2000; 67(4): 982-5.
[http://dx.doi.org/10.1086/303078] [PMID: 10986043]
[104]
Moss J, Howlin P. Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intellect Disabil Res 2009; 53(10): 852-73.
[http://dx.doi.org/10.1111/j.1365-2788.2009.01197.x] [PMID: 19708861]
[105]
Tsujimura K, Abematsu M, Kohyama J, Namihira M, Nakashima K. Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2. Exp Neurol 2009; 219(1): 104-11.
[http://dx.doi.org/10.1016/j.expneurol.2009.05.001] [PMID: 19427855]
[106]
Zhao LY, Zhang J, Guo B, et al. MECP2 promotes cell proliferation by activating ERK1/2 and inhibiting p38 activity in human hepatocellular carcinoma HEPG2 cells. Cell Mol Biol 2013; 59(Suppl. 59): OL1876-81.
[PMID: 24199952]
[107]
Mellios N, Feldman DA, Sheridan SD, et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry 2018; 23(4): 1051-65.
[http://dx.doi.org/10.1038/mp.2017.86] [PMID: 28439102]
[108]
Yoon HS, Ramachandiran S, Chacko MA, Monks TJ, Lau SS. Tuberous sclerosis-2 tumor suppressor modulates ERK and B-Raf activity in transformed renal epithelial cells. Am J Physiol Renal Physiol 2004; 286(2): F417-24.
[http://dx.doi.org/10.1152/ajprenal.00234.2003] [PMID: 14612383]
[109]
Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121(2): 179-93.
[http://dx.doi.org/10.1016/j.cell.2005.02.031] [PMID: 15851026]
[110]
Ma L, Teruya-Feldstein J, Bonner P, et al. Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 2007; 67(15): 7106-12.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4798] [PMID: 17671177]
[111]
Stornetta RL, Zhu JJ. Ras and Rap signaling in synaptic plasticity and mental disorders. Neuroscientist 2011; 17(1): 54-78.
[http://dx.doi.org/10.1177/1073858410365562] [PMID: 20431046]
[112]
Shilyansky C, Lee YS, Silva AJ. Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annu Rev Neurosci 2010; 33: 221-43.
[http://dx.doi.org/10.1146/annurev-neuro-060909-153215] [PMID: 20345245]
[113]
Ferner RE. The neurofibromatoses. Pract Neurol 2010; 10(2): 82-93.
[http://dx.doi.org/10.1136/jnnp.2010.206532] [PMID: 20308235]
[114]
Li W, Cui Y, Kushner SA, et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005; 15(21): 1961-7.
[http://dx.doi.org/10.1016/j.cub.2005.09.043] [PMID: 16271875]
[115]
Silva AJ, Frankland PW, Marowitz Z, et al. A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet 1997; 15(3): 281-4.
[http://dx.doi.org/10.1038/ng0397-281] [PMID: 9054942]
[116]
Costa RM, Federov NB, Kogan JH, et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. nature 2002; 415(6871): 526-30.
[117]
Park CS, Zhong L, Tang SJ. Aberrant expression of synaptic plasticity-related genes in the NF1+/- mouse hippocampus. J Neurosci Res 2009; 87(14): 3107-19.
[http://dx.doi.org/10.1002/jnr.22134] [PMID: 19475561]
[118]
Miller S, Yasuda M, Coats JK, Jones Y, Martone ME, Mayford M. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 2002; 36(3): 507-19.
[http://dx.doi.org/10.1016/S0896-6273(02)00978-9] [PMID: 12408852]
[119]
Darnell JC, Van Driesche SJ, Zhang C, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 2011; 146(2): 247-61.
[http://dx.doi.org/10.1016/j.cell.2011.06.013] [PMID: 21784246]
[120]
Berryer MH, Hamdan FF, Klitten LL, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat 2013; 34(2): 385-94.
[http://dx.doi.org/10.1002/humu.22248] [PMID: 23161826]
[121]
Xing J, Kimura H, Wang C, et al. Resequencing and association analysis of six PSD-95-related genes as possible susceptibility genes for schizophrenia and autism spectrum disorders. Sci Rep 2016; 6(1): 27491.
[http://dx.doi.org/10.1038/srep27491] [PMID: 27271353]
[122]
Rumbaugh G, Adams JP, Kim JH, Huganir RL. SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci USA 2006; 103(12): 4344-51.
[http://dx.doi.org/10.1073/pnas.0600084103] [PMID: 16537406]
[123]
Clement JP, Aceti M, Creson TK, et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 2012; 151(4): 709-23.
[http://dx.doi.org/10.1016/j.cell.2012.08.045] [PMID: 23141534]
[124]
Ozkan ED, Creson TK, Kramár EA, et al. Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron 2014; 82(6): 1317-33.
[http://dx.doi.org/10.1016/j.neuron.2014.05.015] [PMID: 24945774]
[125]
Aceti M, Creson TK, Vaissiere T, et al. Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biol Psychiatry 2015; 77(9): 805-15.
[http://dx.doi.org/10.1016/j.biopsych.2014.08.001] [PMID: 25444158]
[126]
Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485(7397): 237-41.
[http://dx.doi.org/10.1038/nature10945] [PMID: 22495306]
[127]
Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008; 82(2): 477-88.
[http://dx.doi.org/10.1016/j.ajhg.2007.12.009] [PMID: 18252227]
[128]
Steinman KJ, Spence SJ, Ramocki MB, et al. Simons VIP Consortium. 16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A 2016; 170(11): 2943-55.
[http://dx.doi.org/10.1002/ajmg.a.37820] [PMID: 27410714]
[129]
Kolli S, Zito CI, Mossink MH, Wiemer EA, Bennett AM. The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling. J Biol Chem 2004; 279(28): 29374-85.
[http://dx.doi.org/10.1074/jbc.M313955200] [PMID: 15133037]
[130]
Berger W, Steiner E, Grusch M, Elbling L, Micksche M. Vaults and the major vault protein: novel roles in signal pathway regulation and immunity. Cell Mol Life Sci 2009; 66(1): 43-61.
[http://dx.doi.org/10.1007/s00018-008-8364-z] [PMID: 18759128]
[131]
Ip JPK, Nagakura I, Petravicz J, Li K, Wiemer EAC, Sur M. Major vault protein, a candidate gene in 16p11. 2 microdeletionsyndrome, is required for the homeostatic regulation of visual cortical plasticity. J Neurosci 2018; 38(16): 3890-900.
[http://dx.doi.org/10.1523/JNEUROSCI.2034-17.2018] [PMID: 29540554]
[132]
Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 2004; 5(3): 173-83.
[http://dx.doi.org/10.1038/nrn1346] [PMID: 14976517]
[133]
Tidyman WE, Rauen KA. Pathogenetics of the RASopathies. Hum Mol Genet 2016; 25(R2): R123-32.
[http://dx.doi.org/10.1093/hmg/ddw191] [PMID: 27412009]
[134]
Borrie SC, Brems H, Legius E, Bagni C. Cognitive dysfunctions in intellectual disabilities: the contributions of the Ras-MAPK and PI3K-AKT-mTOR pathways. Annu Rev Genomics Hum Genet 2017; 18: 115-42.
[http://dx.doi.org/10.1146/annurev-genom-091416-035332] [PMID: 28859574]
[135]
Kalkman HO. Potential opposite roles of the extracellular signal-regulated kinase (ERK) pathway in autism spectrum and bipolar disorders. Neurosci Biobehav Rev 2012; 36(10): 2206-13.
[http://dx.doi.org/10.1016/j.neubiorev.2012.07.008] [PMID: 22884480]
[136]
Pellerin D, Çaku A, Fradet M, Bouvier P, Dubé J, Corbin F. Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet’s signaling cascades as new outcome measures in clinical trials. Biomarkers 2016; 21(6): 497-508.
[http://dx.doi.org/10.3109/1354750X.2016.1160289] [PMID: 27058300]
[137]
Pucilowska J, Vithayathil J, Pagani M, et al. Pharmacological inhibition of ERK signaling rescues pathophysiology and behavioral phenotype associated with 16p11. 2 chromosomal deletion in mice. J Neurosci 2018; 38(30): 6640-52.
[http://dx.doi.org/10.1523/JNEUROSCI.0515-17.2018] [PMID: 29934348]
[138]
Inoue S, Moriya M, Watanabe Y, et al. New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. Hum Mol Genet 2014; 23(24): 6553-66.
[http://dx.doi.org/10.1093/hmg/ddu376] [PMID: 25035421]
[139]
Feld M, Krawczyk MC, Sol Fustiñana M, et al. Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer’s disease. J Alzheimers Dis 2014; 40(1): 69-82.
[http://dx.doi.org/10.3233/JAD-131076] [PMID: 24334722]
[140]
Bartolomé F, de Las Cuevas N, Muñoz U, Bermejo F, Martín-Requero A. Impaired apoptosis in lymphoblasts from Alzheimer’s disease patients: cross-talk of Ca2+/calmodulin and ERK1/2 signaling pathways. Cell Mol Life Sci 2007; 64(11): 1437-48.
[http://dx.doi.org/10.1007/s00018-007-7081-3] [PMID: 17502994]
[141]
Pei JJ, Gong CX, An WL, et al. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer’s disease. Am J Pathol 2003; 163(3): 845-58.
[http://dx.doi.org/10.1016/S0002-9440(10)63445-1] [PMID: 12937126]
[142]
Chong YH, Shin YJ, Lee EO, Kayed R, Glabe CG, Tenner AJ. ERK1/2 activation mediates Abeta oligomer-induced neurotoxicity via caspase-3 activation and tau cleavage in rat organotypic hippocampal slice cultures. J Biol Chem 2006; 281(29): 20315-25.
[http://dx.doi.org/10.1074/jbc.M601016200] [PMID: 16714296]
[143]
Andersen JM, Myhre O, Fonnum F. Discussion of the role of the extracellular signal-regulated kinase-phospholipase A2 pathway in production of reactive oxygen species in Alzheimer’s disease. Neurochem Res 2003; 28(2): 319-26.
[http://dx.doi.org/10.1023/A:1022389503105] [PMID: 12608704]
[144]
Li J, Fan Y, Zhang YN, et al. The Raf-1 inhibitor GW5074 and the ERK1/2 pathway inhibitor U0126 ameliorate PC12 cells apoptosis induced by 6-hydroxydopamine. Die Pharmazie-An International Journal of Pharmaceutical Sciences 2012; 67(8): 718-24.
[PMID: 22957439]
[145]
Xia Q, Hu Q, Wang H, et al. Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia. Cell Death Dis 2015; 6(3): e1702.
[http://dx.doi.org/10.1038/cddis.2015.69] [PMID: 25811799]
[146]
Ahnstedt H, Säveland H, Nilsson O, Edvinsson L. Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway. BMC Neurosci 2011; 12(1): 5.
[http://dx.doi.org/10.1186/1471-2202-12-5] [PMID: 21223556]
[147]
Maddahi A, Ansar S, Chen Q, Edvinsson L. Blockade of the MEK/ERK pathway with a raf inhibitor prevents activation of pro-inflammatory mediators in cerebral arteries and reduction in cerebral blood flow after subarachnoid hemorrhage in a rat model. J Cereb Blood Flow Metab 2011; 31(1): 144-54.
[http://dx.doi.org/10.1038/jcbfm.2010.62] [PMID: 20424636]
[148]
Vikman P, Ansar S, Henriksson M, Stenman E, Edvinsson L. Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries. Exp Brain Res 2007; 183(4): 499-510.
[http://dx.doi.org/10.1007/s00221-007-1062-5] [PMID: 17828393]
[149]
Maddahi A, Kruse LS, Chen QW, Edvinsson L. The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat. J Neuroinflammation 2011; 8(1): 107.
[http://dx.doi.org/10.1186/1742-2094-8-107] [PMID: 21871121]
[150]
Nissan MH, Rosen N, Solit DB. ERK pathway inhibitors: how low should we go? Cancer Discov 2013; 3(7): 719-21.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0245] [PMID: 23847348]
[151]
Chapman PB, Hauschild A, Robert C, et al. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507-16.
[http://dx.doi.org/10.1056/NEJMoa1103782] [PMID: 21639808]
[152]
Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci USA 2010; 107(33): 14903-8.
[http://dx.doi.org/10.1073/pnas.1008990107] [PMID: 20668238]
[153]
Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379(9829): 1893-901.
[http://dx.doi.org/10.1016/S0140-6736(12)60398-5] [PMID: 22608338]
[154]
Hubina E, Nanzer AM, Hanson MR, et al. Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. Eur J Endocrinol 2006; 155(2): 371-9.
[http://dx.doi.org/10.1530/eje.1.02213] [PMID: 16868153]
[155]
Hofland LJ, van der Hoek J, van Koetsveld PM, et al. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab 2004; 89(4): 1577-85.
[http://dx.doi.org/10.1210/jc.2003-031344] [PMID: 15070915]
[156]
Han H, Zhan Z, Xu J, Song Z. TMEFF2 inhibits pancreatic cancer cells proliferation, migration, and invasion by suppressing phosphorylation of the MAPK signaling pathway. OncoTargets Ther 2019; 12: 11371-82.
[http://dx.doi.org/10.2147/OTT.S210619] [PMID: 31920328]
[157]
Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 2012; 16(1): 103-19.
[http://dx.doi.org/10.1517/14728222.2011.645805] [PMID: 22239440]
[158]
Kohno M, Pouyssegur J. Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog Cell Cycle Res 2003; 5: 219-24.
[PMID: 14593716]
[159]
Girault JA, Valjent E, Caboche J, Hervé D. ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 2007; 7(1): 77-85.
[http://dx.doi.org/10.1016/j.coph.2006.08.012] [PMID: 17085074]
[160]
Deng W, Sui H, Wang Q, et al. A Chinese herbal formula, Yi-Qi-Fu-Sheng, inhibits migration/invasion of colorectal cancer by down-regulating MMP-2/9 via inhibiting the activation of ERK/MAPK signaling pathways. BMC Complement Altern Med 2013; 13(1): 65.
[http://dx.doi.org/10.1186/1472-6882-13-65] [PMID: 23506655]
[161]
Wang S, Huang X, Li Y, et al. RN181 suppresses hepatocellular carcinoma growth by inhibition of the ERK/MAPK pathway. Hepatology 2011; 53(6): 1932-42.
[http://dx.doi.org/10.1002/hep.24291] [PMID: 21391225]
[162]
Kritsanawong S, Innajak S, Imoto M, Watanapokasin R. Antiproliferative and apoptosis induction of α-mangostin in T47D breast cancer cells. Int J Oncol 2016; 48(5): 2155-65.
[http://dx.doi.org/10.3892/ijo.2016.3399] [PMID: 26892433]
[163]
Lai H, Wang Y, Duan F, et al. Krukovine suppresses KRAS-mutated lung Cancer cell growth and proliferation by inhibiting the RAF-ERK pathway and inactivating AKT pathway. Front Pharmacol 2018; 9: 958.
[http://dx.doi.org/10.3389/fphar.2018.00958] [PMID: 30186180]
[164]
Yu Y, Fu X, Ran Q, et al. Globularifolin exerts anticancer effects on glioma U87 cells through inhibition of Akt/mTOR and MEK/ERK signaling pathways in vitro and inhibits tumor growth in vivo. Biochimie 2017; 142: 144-51.
[http://dx.doi.org/10.1016/j.biochi.2017.09.005] [PMID: 28912095]
[165]
Stevens PD, Wen YA, Xiong X, et al. Erbin suppresses KSR1-mediated RAS/RAF signaling and tumorigenesis in colorectal cancer. Cancer Res 2018; 78(17): 4839-52.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3629] [PMID: 29980571]
[166]
Sullivan RJ, Infante JR, Janku F, et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov 2018; 8(2): 184-95.
[http://dx.doi.org/10.1158/2159-8290.CD-17-1119] [PMID: 29247021]
[167]
Infante JR, Janku F, Tolcher AW, et al. Dose escalation stage of a first-in-class phase I study of the novel oral ERK 1/2 kinase inhibitor BVD-523 (ulixertinib) in patients with advanced solid tumors.
[168]
Li BT, Janku F, Patel MR, et al. First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study. J Clin Oncol 2017; 35(15)(Suppl.): 2508-12508.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.2508] [PMID: 28524777]
[169]
Chin HM, Lai DK, Falchook GS. Extracellular signal-regulated kinase (ERK) inhibitors in oncology clinical trials. Journal of Immunotherapy and Precision Oncology 2019; 2(1): 10.
[http://dx.doi.org/10.4103/JIPO.JIPO_17_18]
[170]
Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov 2014; 13(12): 928-42.
[http://dx.doi.org/10.1038/nrd4281] [PMID: 25435214]
[171]
Ryan MB, Der CJ, Wang-Gillam A, Cox AD. Targeting RAS-mutant cancers: is ERK the key? Trends Cancer 2015; 1(3): 183-98.
[http://dx.doi.org/10.1016/j.trecan.2015.10.001] [PMID: 26858988]
[172]
Burrows F, Kessler L, Chen J, et al. KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors. Experimental and Molecular Therapeutics 2017; 77(13): 5168.
[173]
Burrows FJ, Kessler L, Wu T, et al. 11q13 amplification selects for sensitivity to the ERK inhibitor KO-947 in squamous cell carcinomas. Experimental and Molecular Therapeutics 2018; 78(13): 3885.
[174]
Kessler L, Wu T, Guo X, et al. KO-947, a potent and selective ERK inhibitor with slow dissociation kinetics. Poster ENA 2016; 69: S126.
[175]
Boshuizen J, Koopman LA, Krijgsman O, et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat Med 2018; 24(2): 203-12.
[http://dx.doi.org/10.1038/nm.4472] [PMID: 29334371]
[176]
Halder AK, Giri AK, Cordeiro MNDS. Multi-Target Chemometric Modelling, Fragment Analysis and Virtual Screening with ERK Inhibitors as Potential Anticancer Agents. Molecules 2019; 24(21): 3909.
[http://dx.doi.org/10.3390/molecules24213909] [PMID: 31671605]
[177]
Bhagwat SV, McMillen WT, Cai S, et al. Discovery of LY3214996, a selective and novel ERK1/2 inhibitor with potent antitumor activities in cancer models with MAPK pathway alterations. Cancer Res 2017; 77(13 Supplement): 4973.
[178]
Pant S, Bendell JC, Sullivan RJ, et al. A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts). J Clinical Oncol 2019; 37(15_suppl): 3001.
[179]
Liu B, Fu L, Zhang C, et al. Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer. Oncotarget 2015; 6(9): 6762-75.
[http://dx.doi.org/10.18632/oncotarget.3105] [PMID: 25742792]
[180]
Roskoski R. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res 2019; 142: 151-68.
[http://dx.doi.org/10.1016/j.phrs.2019.01.039]
[181]
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(4): 552-62.
[http://dx.doi.org/10.1016/j.apsb.2018.01.008] [PMID: 30109180]
[182]
Nunn PA, Berner B, Masjedizadeh MR. PRINCIPIA BIOPHARMA Inc, assignee. Compositions for ileo-jejunal drug delivery. United States patent application US, 2018.
[183]
Merchant M, Chan J, Orr C, et al. 387 Combination of the ERK inhibitor GDC-0994 with the MEK inhibitor cobimetinib significantly enhances anti-tumor activity in KRAS and BRAF mutant tumor models. Eur J Cancer 2014; 50: 124.
[http://dx.doi.org/10.1016/S0959-8049(14)70513-1]
[184]
Miermont AM, Pflicke H, Guan H, Chinnasamy H, Thomas C, Rudloff U. Direct inhibition of ERK1/2 by VTX-11e leads to increased induction of apoptosis in a subset of pancreatic cancer cell lines as compared to MEK1/2 inhibition by selumetinib (AZD6244). Cancer Re 2013; 73(8 Supplement): 5538.
[185]
Yu Z, Ye S, Hu G, et al. The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy. Future Med Chem 2015; 7(3): 269-89.
[http://dx.doi.org/10.4155/fmc.14.143] [PMID: 25826360]
[186]
Swamy N, Sundaresha HM. Women, Infants Hospital of RI Inc, assignee. Compositions and Methods for Cancer Treatment. United States patent application US, 2010.
[187]
Swamy N. Women, Infants Hospital of RI Inc, assignee. Compositions and methods for cancer treatment. United States patent US 8,853,188, 2014.
[188]
Lazzerini PE, Natale M, Gianchecchi E, et al. Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system. J Mol Med (Berl) 2012; 90(3): 331-42.
[http://dx.doi.org/10.1007/s00109-011-0824-5] [PMID: 22033526]
[189]
Atmaca H, Özkan AN, Zora M. Novel ferrocenyl pyrazoles inhibit breast cancer cell viability via induction of apoptosis and inhibition of PI3K/Akt and ERK1/2 signaling. Chem Biol Interact 2017; 263: 28-35.
[http://dx.doi.org/10.1016/j.cbi.2016.12.010] [PMID: 27989600]
[190]
Ohori M. ERK inhibitors as a potential new therapy for rheumatoid arthritis. Drug News Perspect 2008; 21(5): 245-50.
[http://dx.doi.org/10.1358/dnp.2008.21.5.1219006] [PMID: 18596988]