Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway
MAPK refers to a group of serine/threonine kinases found in eukaryotic cells. It is distributed widely in the cytoplasm and can be divided into four subfamilies:
- Extracellular signal-regulated kinases (ERKs)
- p38 MAPKs
- c-Jun N-terminal kinases (JNKs)
- ERK5
MAPK signaling is crucial during development, where thyroid hormones regulate cellular differentiation, especially in the brain and skeletal system.
T3-mediated activation of MAPK directly controls neural differentiation by regulating the expression of genes critical for neurogenesis.
In skeletal tissue, thyroid hormones control osteoblast proliferation and activity via MAPK, which is essential for bone development and maintenance
Dysregulation of MAPK signaling is closely associated with thyroid-related diseases.
The MAPK pathway plays a significant role in cancer due to its involvement in cell proliferation, survival, differentiation, and stress responses. Dysregulation of this pathway is common in many cancers and contributes to tumor growth and progression.
Fluoride
Ai F, Wang S, Ye L, Wan W, Zhou X, Liu M, Mo K, Lu Y, Wei N, Guan Z, Liu Y - "Chondroitin sulfate protects against synaptic impairment caused by fluorosis through the Erk1/2-MMP-9 signaling pathway" Sci Rep 15(1):29760 (2025) doi: 10.1038/s41598-025-14631-7
https://www.nature.com/articles/s41598-025-14631-7
Anderson NG, Kilgour E, Sturgill TW - "Activation of mitogen-activated protein kinase in BC3H1 myocytes by fluoroaluminate" J Biol Chem 266(16):10131(1991) PMID: 1709925.
https://www.jbc.org/content/266/16/10131.long
Bogatcheva NV, Wang P, Birukova AA, Verin AD, Garcia JG - "Mechanism of fluoride-induced MAP kinase activation in pulmonary artery endothelial cells" Am J Physiol Lung Cell Mol Physiol 290(6):L1139-45 (2006) doi: 10.1152/ajplung.00161.2005
https://journals.physiology.org/doi/ful ... 00161.2005
Cao J, Chen J, Wang J, Klerks P, Xie L - "Effects of sodium fluoride on MAPKs signaling pathway in the gills of a freshwater teleost, Cyprinus carpio" Aquat Toxicol 152:164-72 (2014) doi: 10.1016/j.aquatox.2014.04.007
https://www.sciencedirect.com/science/a ... 5X14001362
Chen J, Niu Q, Xia T, Zhou G, Li P, Zhao Q, Xu C, Dong L, Zhang S, Wang A - "ERK1/2-mediated disruption of BDNF-TrkB signaling causes synaptic impairment contributing to fluoride-induced developmental neurotoxicity" Toxicology 410:222-230 (2018). doi: 10.1016/j.tox.2018.08.009
https://www.sciencedirect.com/science/a ... 3X18302531
"These results suggest that ERK1/2 plays a vital role in fluoride-induced impairment of synaptogenesis through interfering with BDNF-TrkB signaling."
Chen Q, Wang Z, Xiong Y, Zou X, Liu Z - "Comparative study of p38 MAPK signal transduction pathway of peripheral blood mononuclear cells from patients with coal-combustion-type fluorosis with and without high hair selenium levels" Int J Hyg Environ Health 213(5):381-6 (2010) doi: 10.1016/j.ijheh.2010.06.002 [co-factor selenium]
"The mRNA and protein level of p53 was significantly higher in high fluoride+high selenium group than that in other two groups."
Chen L, Kuang P, Liu H, Wei Q, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L - "Sodium Fluoride (NaF) Induces Inflammatory Responses Via Activating MAPKs/NF-κB Signaling Pathway and Reducing Anti-inflammatory Cytokine Expression in the Mouse Liver" Biol Trace Elem Res 189(1):157-171 (2019) doi: 10.1007/s12011-018-1458-z. Epub 2018 Jul 30. PMID: 30062462
https://pubmed.ncbi.nlm.nih.gov/30062462/
He WW, Zeng XX, Qi XL, Gui CZ, Liao W, Tu X, Deng J, Dong YT, Hong W, He Y, Xiao Y, Guan ZZ - "Regulating effect of miR-132-3p on the changes of MAPK pathway in rat brains and SH-SY5Y cells exposed to excessive fluoride by targeting expression of MAPK1" Ecotoxicol Environ Saf 279:116467 (2024) doi: 10.1016/j.ecoenv.2024.116467
https://www.sciencedirect.com/science/a ... 1324005438
Kuang P, Cui H, Yu L - "Sodium fluoride suppresses spleen development through MAPK/ERK signaling pathway in mice" Ecotoxicol Environ Saf 241:113764 (2022) doi: 10.1016/j.ecoenv.2022.113764
https://www.sciencedirect.com/science/a ... 1322006042
"Additionally, the mRNA and protein levels of MEK1/2 were increased on the 21st day of the experiment, while reduced on the 42nd day."
Liang Q, Li H, Deng J, Zhang T, Ma Y, Zhang K - "Changes of RAGE/p38MAPK/NF-κB signaling pathway in brain tissue of rats with subchronic fluorosis and the protective effects of Ginkgo biloba extract and RAGE blocker" Acta Endem Dis (3):245-253 (2024) PFPC Library
http://218.28.6.71:81/Qikan/Article/Det ... 7110142589
"The Western blotting results showed that compared with the relative protein expression levels of RAGE, HMGB1, NF-κB, p38MAPK, p-p38MAPK, IL-6,and TNF-α in the C group, the levels of above indicators in the HF group and the levels of RAGE, HMGB1, NF-κB, p-p38MAPK, and IL-6 in the LF group were up-regulated (P<0.05)...The central nervous system injury caused by subchronic fluorosis may be related to the activation of RAGE/p38-MAPK/NF-κB signaling pathway, which can impair the learning and memory ability of rats."
Li Y, Ma T, Lv X, Qiu Z, Li S, Qi J, Wei C - "Fluoride stimulates the MAPK pathway to regulate endoplasmic reticulum stress and heat shock proteins to induce duodenal toxicity in chickens" Poult Sci 103(12):104408 (2024) doi: 10.1016/j.psj.2024.104408.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11550079/
Liu Y, Gao Q, Wu C, Long Y, Guan Z - "Expression of extracellular regulated protein kinase in brain tissue of rats with chronic fluorine poisoning and changes in learning and memory abilities of rats" Chin J Endemiol (1):32-35 (2009) PFPC Library
"Long-term exposure of excessive fluoride induces the change of expression and activating rate of the ERK1/2 in rat brains, leading to the decreased capacity of learning and memory."
Liu Yanjie - "The role of MAPK signal transduction pathway in the pathogenesis of brain injury in chronic fluorosis rats" (2011)(Doctoral dissertation).
https://xueshu.baidu.com/usercenter/pap ... ebcf02d119
viewtopic.php?f=23&t=2117
Liu Y, Liang Y, Yang C, Shi R, Lu W, Wang X, Wang R, Xia Q, Ma S - "A deep insight into the transcriptome of midgut and fat body reveals the toxic mechanism of fluoride exposure in silkworm" Chemosphere 262:127891 (2021) doi: 10.1016/j.chemosphere.2020.127891
https://www.sciencedirect.com/science/a ... 3520320865
" The MAPK signal pathway was stimulated via phosphorylation signal transduction."
Liu Y, Chang J, Yang C, Zhang T, Chen X, Shi R, Liang Y, Xia Q, Ma S - "Genome-wide CRISPR-Cas9 screening in Bombyx mori reveals the toxicological mechanisms of environmental pollutants, fluoride and cadmium" J Hazard Mater 410:124666. doi: 10.1016/j.jhazmat.2020.124666
https://linkinghub.elsevier.com/retriev ... 20)32656-X
"Functional analysis of the resistant- and sensitive-genes demonstrates enrichment of multiple signaling pathways, among which the MAPK signaling pathway and DNA damage and repair are both required for fluoride- or cadmium-induced cell death."
Lv Y, Yao J, Wang Y, Bai G, Lin C, Tu C - "Co-exposure to fluoride and sulfur dioxide induces abnormal enamel mineralization in rats via the FGF9-mediated MAPK signaling pathway" Environ Res 250:118527 (2024) doi: 10.1016/j.envres.2024.118527
https://www.sciencedirect.com/science/a ... 5124004316
Ma Y, Zhang K, Ren F, Wang J - "Developmental fluoride exposure influenced rat's splenic development and cell cycle via disruption of the ERK signal pathway" Chemosphere 187:173-180 (2017) doi: 10.1016/j.chemosphere.2017.08.067
https://linkinghub.elsevier.com/retriev ... 3517312900
Misra UK, Gawdi G, Pizzo SV - "Beryllium fluoride-induced cell proliferation: a process requiring P21(ras)-dependent activated signal transduction and NF-kappaB-dependent gene regulation" J Leukoc Biol 71(3):487-94 (2000)
https://pubmed.ncbi.nlm.nih.gov/11867686/
https://jlb.onlinelibrary.wiley.com/doi ... m%3Apubmed
"We studied the effect of beryllium fluoride on murine peritoneal macrophages and determined its effects on signal transduction and genetic regulation...A significant increase in the levels of MEK1, ERK1, p38 MAPK, and JNK phosphorylation was observed in BeF(2)-exposed macrophages...We conclude that BeF(2) at low concentration exerts its mitogenic effects in peritoneal macrophages by elevating [Ca(2)(+)](i), which triggers the activation of p21(ras)-dependent MAPK signaling cascades."
Note: G/q 11
Ommati MM, Sabouri S, Sun Z, Zamiri MJ, Retana-Marquez S, Nategh Ahmadi H, Zuo Q, Eftekhari A, Juárez-Rojas L, Asefi Y, Lei L, Cui SG, Jadidi MH, Wang HW, Heidari R - "Inactivation of Mst/Nrf2/Keap1 signaling flexibly mitigates MAPK/NQO-HO1 activation in the reproductive axis of experimental fluorosis" Ecotoxicol Environ Saf 271:115947 (2024). doi: 10.1016/j.ecoenv.2024.115947
https://www.sciencedirect.com/science/a ... 1324000228
Panneerselvam L, Govindarajan V, Ameeramja J, Nair HR, Perumal E - "Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats" Biochimie 119:27-35 (2015) doi: 10.1016/j.biochi.2015.10.002
https://linkinghub.elsevier.com/retriev ... 8415003120
"An increased cardiac expression of Nox4 and p38α MAPK in F(-) treated rats indicates the oxidative and apoptotic damage."
Parada-Cruz B, Aztatzi-Aguilar OG, Ramírez-Martínez G, Jacobo-Estrada TL, Cárdenas-González M, Escamilla-Rivera V, Martínez-Olivas MA, Narváez-Morales J, Ávila-Rojas SH, Álvarez-Salas LM, Barbier O - "Inflammation- and cancer-related microRNAs in rat renal cortex after subchronic exposure to fluoride" Chem Biol Interact 379:110519 (2023) doi: 10.1016/j.cbi.2023.110519
https://www.sciencedirect.com/science/a ... 9723001862
Pei J, Xu J, Gao Y, Sun H, Lv C, Jiang Y, Sun W, Jiang W, Qu L, Jiang L, Sun D - "Identification of pathogenesis-related microRNA profiles in skeletal fluorosis" Fluoride 52(1):29-41 (2019)
https://www.fluorideresearch.org/epub/files/008.pdf
"Pathway analysis of miRNAs by KEGG revealed the MAPK signaling pathway, pathways in cancer, the PI3K-Akt signaling pathway, proteoglycans in cancer, and the endocytosis pathway to be regulated by the differentially expressed miRNAs."
Qiu Z, Liu Y, Feng J, Qi X, Li Y, Deng C, Guan Z - "Immunohistochemical changes of extracellular signal-regulated protein kinase 5 in the brain of rats with chronic fluoride poisoning" Prev Control Endem Dis China (7):724-725, 759 (2016) PFPC LIbrary
"We investigated (ERK5) in the mitogen-activated protein kinase (MAPK) signal transduction pathway in different functional areas of the brain in rats with chronic fluoride poisoning...Chronic fluoride poisoning leads to increased expression levels of P-ERK5 and ERK5 proteins in the cerebral cortex and hippocampal CA3 and CA4 regions of rats, which may be related to the changes in immune tissues in the brain of rats with chronic fluoride poisoning."
Ran L, Gui C, Huang X, Guan Z - "Study on ERK/p-90RSK signal transduction pathway in brain tissue of rats with coal-burning fluorosis" Guizhou Med J. (1):8-11 (2013) PFPC Library
"Coal-burning pollution-induced fluorosis can cause excessive activation of the ERK signal transduction pathway in rat brain tissue."
Ran L, Gui C, Wu C, et al. - "The relationship between intelligence and brain ERK1/2 expression in rats with coal-burning fluorosis" Chinese Public Health 6(10):1228-1229 (2010) PFPC Library
"Compared to the control, the increase in expression of phospho-Erk1/2 was observed at protein and mRNA level in the rats with fluoride exposure, which had a correlation with the decreased capacity of learning and memory...The fluorosis due to coal-burning pollution can induce declines of learning and memory ability in rats, in which the mechanism may be related to the activation of ERK1/2 phosphorylation."
Refsnes M, Skuland T, Låg M, Schwarze PE, Øvrevik J - "Differential NF-κB and MAPK activation underlies fluoride- and TPA-mediated CXCL8 (IL-8) induction in lung epithelial cells" J Inflamm Res 7:169-85 (2014) doi: 10.2147/JIR.S69646
https://pmc.ncbi.nlm.nih.gov/articles/PMC4270361/
Sun L, Gao Y, Zhang W, Liu X, Li B, Cui X, Sun D - "Mechanisms Underlying Endothelin-1 Level Elevations Caused by Excessive Fluoride Exposure" Cell Physiol Biochem 40(5):861-873 (2016).doi: 10.1159/000453145
https://karger.com/cpb/article/40/5/861 ... in-1-Level
"Excessive fluoride exposure leads to characteristic endothelial damage (vacuoles), thoracic aorta hardening, and plasma ET-1 level elevations in rabbits. In addition, the ROS-RAS-MEK1/2-pERK1/2/ERK1/2 pathway plays a crucial—and at least partial—role in ET-1 over-expression, which is promoted by excessive fluoride exposure."
Tian Y, Xiao Y, Wang B, Sun C, Tang K, Sun F - "Vitamin E and lycopene reduce coal burning fluorosis-induced spermatogenic cell apoptosis via oxidative stress-mediated JNK and ERK signaling pathways" Biosci Rep 38(4):BSR20171003 (2018) doi: 10.1042/BSR20171003. PMID: 29273675; PMCID: PMC6066653.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066653/
Wang X, Bai G, Tian Y - "Research progress on molecular signaling pathways in the pathogenesis of dental fluorosis" Chin J Endemiol (2):159-164 (2023) PFPC Library
Wang C, et al. - "Expression of Erk kinase, AMPA receptor subunits GluR1 and GluR2, and protection of chondroitin sulfate in the brain of rats with chronic fluorosis" Chin J Endemiol 38(6):446-452 (2019) PFPC Library
http://218.28.6.71:81/Qikan/Article/Det ... 7100350325
"The protein levels of Erk1/2 and phospho-Erk1/2 in the low dose and high dose fluoride groups were significantly increased...The CNS injury caused by chronic fluorosis may be related to GluRl and GluR2 activated Erk1/2 signaling pathway."
Wang F, Li C, Qin Y, Han X, Gao J, Zhang A, Luo P, Pan X - "Analysis of the microRNA Profile of Coal-Burning Endemic Fluorosis Using Deep Sequencing and Bioinformatic Approaches" Bull Environ Contam Toxicol 103(1):56-63 (2019) doi: 10.1007/s00128-019-02660-8
https://link.springer.com/article/10.10 ... 19-02660-8
"KEGG pathway enrichment analyses of downregulated genes revealed that they were mainly enriched in the Ras signaling pathway, the phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) signaling pathway, pathways in cancer, endocytosis, the Rap1 signaling pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway."
Weng Q, Yi F, Yu Y, Ge S, Liu S, Zhang Y - "Altered miRNA expression profiling in enamel organ of fluoride affected rat embryos" Ecotoxicol Environ Saf. 210:111876 (2021)
https://pubmed.ncbi.nlm.nih.gov/33418158/
"The functional annotation of the target genes of 39 DE miRNAs showed significant enrichment in metabolic process, cell differentiation, calcium signaling pathway, and mitogen-activated protein kinase(MAPK) signaling pathway terms."
Yan Nan - "Fluorine promotes the secretion of inflammatory factors in microglia by activating MAPK and NF-κB signaling pathways" China Medical University, Master's Thesis (2018)
http://61.54.243.197:8089/KCMS/detail/d ... e=CDFD2019
viewtopic.php?f=30&t=5264
Yang H, Xing R, Liu S, Yu H, Li P - "Analysis of the protective effects of γ-aminobutyric acid during fluoride-induced hypothyroidism in male Kunming mice" Pharm Biol 57(1):29-37 (2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346718/
"In this study, after exposing mice to NaF, ERK1/2 expression increased significantly, suggesting that fluoride mediates apoptosis in thyroid follicular epithelial cells through the sustained activation of ERK1/2. The daily administration of 50 mg/kg GABA over 14 days significantly inhibited ERK1/2, demonstrating that GABA mitigates fluoride-induced apoptosis by inhibiting the activation of ERK1/2."
Yang L, Jin P, Wang X, Zhou Q, Lin X, Xi S - "Fluoride activates microglia, secretes inflammatory factors and influences synaptic neuron plasticity in the hippocampus of rats" Neurotoxicology 69:108-120 (2018) doi: 10.1016/j.neuro.2018.09.006. Epub 2018 Sep 28. PMID: 30273629
https://pubmed.ncbi.nlm.nih.gov/30273629/
"We found that fluoride exposure activated microglia and increased the expression of DAP12 and TREM2, as well as promoted pro-inflammatory cytokines secretion via ERK/MAPK and P38/MAPK signal pathways."
Yang B, Wang F, Yang X, Yuan X, Yang Y, Chen X, Tian T, Chen F, Tang D, He Z, Liu Y, Li Y - "The Role of SIRT1-BDNF Signaling Pathway in Fluoride-Induced Toxicity for Glial BV-2 Cells" Biol Trace Elem Res (2025) doi: 10.1007/s12011-024-04503-y
https://link.springer.com/article/10.10 ... 24-04503-y
"The fluoride-exposed groups had reduced SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein expression levels, and increased FOXO1A protein expression. SRT1720 mitigated the harmful effects of NaF, stimulated cell proliferation and cell cycle progression, decreased apoptosis, reduced oxidative stress and inflammatory factors, elevated SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein levels, and suppressed FOXO1A protein expression. The results indicate that NaF potentially harms glial cells by suppressing SIRT1 activation, and SIRT1 significantly mitigated the damage."
Xu S, Khoo S, Dang A, Witt S, Do V, Zhen E, Schaefer EM, Cobb MH - "Differential regulation of mitogen-activated protein/ERK kinase (MEK)1 and MEK2 and activation by a Ras-independent mechanism" Mol Endocrinol 11(11):1618-25 (1997) doi: 10.1210/mend.11.11.0010. PMID: 9328344.
https://academic.oup.com/mend/article/1 ... 18/2756758
Zhao L, Su J, Liu S, Li Y, Xi T, Ruan J, Liang KX, Huang R - "MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment" Biochem Biophys Res Commun 542:65-72 (2021) doi: 10.1016/j.bbrc.2020.12.100
https://pubmed.ncbi.nlm.nih.gov/33493990/
"Using this system, we demonstrated that fluoride exposure led to an inhibition of p-MEK and p-ERK1/2 with a subsequent increase in MKP-1 expression in a dose-dependent manner. We further identified, under high dose fluoride, MKP-1 acted as a negative regulator of the fluoride-induced p-ERK1/2 signaling, leading to downregulation of CREB, c-myc, and Elk-1. Our results identify a novel MKP-1/ERK signaling mechanism that regulates dental fluorosis and provide a framework for studying the molecular mechanisms of intervention and fluorosis remodeling under normal and pathological conditions. MKP-1 inhibitors may prove to be a benefit therapeutic strategy for dental fluorosis treatment."
Zhao Y, Pu G, Li Y, Jiang H, Zhang Q, Chen P, Lu Q, Wang M, Yang R - "Serum Levels of CXCR4, SDF-1, MCP-1, NF-κB and ERK1/2 in Patients with Skeletal Fluorosis" Int J Environ Res Public Health 19(24):16555 (2022) doi: 10.3390/ijerph192416555
https://www.mdpi.com/1660-4601/19/24/16555
Zhu WQ, Yu YJ, Xu LN, Ming PP, Shao SY, Qiu J - "Regulation of osteoblast behaviors via cross-talk between Hippo/YAP and MAPK signaling pathway under fluoride exposure" J Mol Med (Berl) 97(7):1003-1017 (2019)
https://pubmed.ncbi.nlm.nih.gov/31055605/
PFAS
Fang X, Feng Y, Shi Z, Dai J - "Alterations of cytokines and MAPK signaling pathways are related to the immunotoxic effect of perfluorononanoic acid" Toxicol Sci 108(2):367-76 (2009) doi: 10.1093/toxsci/kfp019
https://academic.oup.com/toxsci/article ... 67/1666782
Fangninou FF, Yu Z, Li Z, Guadie A, Li W, Xue L, Yin D - "Metastatic effects of environmental carcinogens mediated by MAPK and UPR pathways with an in vivo Drosophila Model" J Hazard Mater 441:129826. doi: 10.1016/j.jhazmat.2022.129826
https://linkinghub.elsevier.com/retriev ... 22)01619-3
Fujiwara N, Yamashita S, Okamoto M, Cooley MA, Ozaki K, Everett ET, Suzuki M - "Perfluorooctanoic acid-induced cell death via the dual roles of ROS-MAPK/ERK signaling in ameloblast-lineage cells" Ecotoxicol Environ Saf 260:115089 (20123). doi: 10.1016/j.ecoenv.2023.115089
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330907/
"MAPK/ERK signaling plays the dual roles (promoting necrosis and suppressing apoptosis) under PFOA treatment. This is the initial report to indicate that PFOA could be considered as a possible causative factor for cryptogenic enamel malformation. Further studies are required to elucidate the mechanisms of PFOA-mediated adverse effects on amelogenesis."
Lee YJ, Choi SY, Yang JH - "PFHxS induces apoptosis of neuronal cells via ERK1/2-mediated pathway" Chemosphere 94:121-7 (2014) doi: 10.1016/j.chemosphere.2013.09.059
https://www.sciencedirect.com/science/a ... 351301299X
Liu Q, Liu Y, Li X, Wang D, Zhang A, Pang J, He J, Chen X, Tang NJ - "Perfluoroalkyl substances promote breast cancer progression via ERα and GPER mediated PI3K/Akt and MAPK/Erk signaling pathways" Ecotoxicol Environ Saf 258:114980 (2023) . doi: 10.1016/j.ecoenv.2023.114980
https://www.sciencedirect.com/science/a ... 1323004840
"Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression."
Lu Y, Luo B, Li J, Dai J - "Perfluorooctanoic acid disrupts the blood-testis barrier and activates the TNFα/p38 MAPK signaling pathway in vivo and in vitro" Arch Toxicol 90(4):971-83 (2016) doi: 10.1007/s00204-015-1492-y
https://link.springer.com/article/10.10 ... 015-1492-y
Lv QY, Wan B, Guo LH, Yang Y, Ren XM, Zhang H - "In vivo immunotoxicity of perfluorooctane sulfonate in BALB/c mice: Identification of T-cell receptor and calcium-mediated signaling pathway disruption through gene expression profiling of the spleen" Chem Biol Interact 240:84-93 (2015) doi: 10.1016/j.cbi.2015.07.015.
https://linkinghub.elsevier.com/retriev ... 15)30029-6
"Global gene expression profiling of mouse spleens and QRT-PCR analyses suggest that PFOS inhibited the expression of genes involved in cell cycle regulation and NRF2-mediated oxidative stress response, and upregulated those in TCR signaling, calcium signaling, and p38/MAPK signaling pathways."
Peng BX, Li F, Mortimer M, Xiao X, Ni Y, Lei Y, Li M, Guo LH - "Perfluorooctanoic acid alternatives hexafluoropropylene oxides exert male reproductive toxicity by disrupting blood-testis barrier" Sci Total Environ 846:157313 (2022) doi: 10.1016/j.scitotenv.2022.157313
https://linkinghub.elsevier.com/retriev ... 22)04411-4
"On the whole, the results indicated HFPO homologues and PFOA induced BTB disruption through upregulation of p-p38/p38 MAPK/MMP-9 pathway."
Qi W, Clark JM, Timme-Laragy AR, Park Y - "Perfluorobutanesulfonic acid (PFBS) potentiates adipogenesis of 3T3-L1 adipocytes" Food Chem Toxicol. 120:340-345 (2018). doi: 10.1016/j.fct.2018.07.031
https://pmc.ncbi.nlm.nih.gov/articles/PMC6169790/
"PFBS significantly activated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) after 4-hour treatment, and PFBS' effect on triglyceride was abolished by U0126, a specific MAPK/ERK kinase (MEK) inhibitor. In conclusion, PFBS increased the adipogenesis of 3T3-L1 adipocytes, in part, via MEK/ERK-dependent pathway."
Qin X, Xie G, Wu X, Xu X, Su M, Yang B - "Prenatal exposure to perfluorooctanoic acid induces nerve growth factor expression in cerebral cortex cells of mouse offspring" Environ Sci Pollut Res Int 25(19):18914-18920 (2018) doi: 10.1007/s11356-018-2117-9
https://link.springer.com/article/10.10 ... 018-2117-9
"Further, immunoblotting assays showed that intracephalic poly (ADP-ribose) polymerase (PARP) and p42/44 mitogen-activated protein kinase (MAPK) proliferation-regulated protein levels were elevated in PFOA-treated cortex cells."
Qiu L, Qian Y, Liu Z, Wang C, Qu J, Wang X, Wang S - "Perfluorooctane sulfonate (PFOS) disrupts blood-testis barrier by down-regulating junction proteins via p38 MAPK/ATF2/MMP9 signaling pathway" Toxicology 373:1-12 (2016) doi: 10.1016/j.tox.2016.11.003
https://linkinghub.elsevier.com/retriev ... 16)30263-3
Shi X, Zhou B - "The role of Nrf2 and MAPK pathways in PFOS-induced oxidative stress in zebrafish embryos Toxicol Sci 115(2):391-400 (2010) doi: 10.1093/toxsci/kfq066
https://academic.oup.com/toxsci/article ... 91/1733986
Wang C, Nie X, Zhang Y, Li T, Mao J, Liu X, Gu Y, Shi J, Xiao J, Wan C, Wu Q - "Reactive oxygen species mediate nitric oxide production through ERK/JNK MAPK signaling in HAPI microglia after PFOS exposure" Toxicol Appl Pharmacol 288(2):143-51 (2015) doi: 10.1016/j.taap.2015.06.012
https://www.sciencedirect.com/science/a ... 8X15300193
Zhang QY, Lai MQ, Chen YK, Zhong MT, Gi M, Wang Q, Xie XL - "Inulin alleviates GenX-induced intestinal injury in mice by modulating the MAPK pathway, cell cycle, and cell adhesion proteins" Environ Pollut 362:124974 (2024) doi: 10.1016/j.envpol.2024.124974
https://linkinghub.elsevier.com/retriev ... 24)01689-0
Zhang J, Ren Z, Chen M - "Immunotoxicity and Transcriptome Analyses of Zebrafish (Danio rerio) Embryos Exposed to 6:2 FTSA" Toxics 11(5):459 (2023) doi: 10.3390/toxics11050459
https://pmc.ncbi.nlm.nih.gov/articles/PMC10222677/
"Transcriptomics showed that genes involved in the MAPK, TLR and NOD-like receptor signaling pathways (hsp70, hsp701, stat1b, irf3, cxcl8b, map3k8, il1b, tnfa and nfkb) were significantly upregulated after 6:2 FTSA exposure, suggesting that 6:2 FTSA might induce immunotoxicity in zebrafish embryos through the TLR/NOD-MAPK pathway."
Zhao Y, Zhao H, Xu H, An P, Ma B, Lu H, Zhou Q, Li X, Xiong Y - "Perfluorooctane sulfonate exposure induces preeclampsia-like syndromes by damaging trophoblast mitochondria in pregnant mice" Ecotoxicol Environ Saf 247:114256 (2022) doi: 10.1016/j.ecoenv.2022.114256
https://www.sciencedirect.com/science/a ... 132201096X
"Mechanistically, these pathological effects on cells resulted from SLC25A5-mediated mitochondrial damages, characterized by excessive ROS generation, decreased ATP production and mitochondrial membrane potential loss, and accompanied by the activation of p38 MAPK and JNK signaling pathways."
Fluoxetine
Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramaugé M, Courtin F, Pierre M - "MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes" J Mol Neurosci 24(2):207-16 (2004). doi: 10.1385/JMN:24:2:207
https://pubmed.ncbi.nlm.nih.gov/15456934/
Abstract
Chronic treatments with antidepressants active on major depressive disorders influence pathways involved in cell survival and plasticity. As astrocytes seem to play a key role in the protection of brain cells, we investigated in these cells the rapid effects of the antidepressant fluoxetine (Prozac) on signaling cascades and gene induction, which probably play a role in neuroprotection. We show here that fluoxetine alone activates the extracellular signal-regulated-protein kinase (Erk) and p38 mitogen-associated protein (MAP) kinase cascades. RT-PCR revealed that genes, modulated in brain by long-term fluoxetine treatment, are rapidly induced by fluoxetine in cultured astrocytes: brain-derived nerve factor (BDNF) and its receptors, glial-derived nerve factor (GDNF) and deiodinase 3 (D3). Induction of D3 by fluoxetine is inhibited by U0126 and SB203580, suggesting that Erk and p38 MAP kinases are involved. Glial-derived nerve factor (GDNF) induction by fluoxetine is prevented by U0126, suggesting that Erk is implicated. Brain-derived nerve factor (BDNF) induction seems mediated by other signaling pathways. In conclusion, we show that fluoxetine alone rapidly activates mitogen activated protein (MAP) kinase cascades in rat astrocytes and that genes involved in neuroprotection are induced in a few hours in a MAP kinase-dependent or -independent manner.
Gq/11 - GNA14
Evans J, Catalano RD, Morgan K, Critchley HO, Millar RP, Jabbour HN - "Prokineticin 1 signaling and gene regulation in early human pregnancy" Endocrinology 149(6):2877-87 (2008) doi: 10.1210/en.2007-1633. Epub 2008 Mar 13. PMID: 18339712; PMCID: PMC2696030.
https://pubmed.ncbi.nlm.nih.gov/18339712/
"COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1. Moreover, expression of COX-2 by PROK1 was dependent on activation of the Gq-phospholipase C-beta-cSrc-epidermal growth factor receptor-MAPK/ERK kinase pathway. "
Goldsmith ZG, Dhanasekaran DN - "G protein regulation of MAPK networks" Oncogene 26(22):3122-42 (2007) doi: 10.1038/sj.onc.1210407. PMID: 17496911.
https://www.nature.com/articles/1210407
Greene EL, Houghton O, Collinsworth G, Garnovskaya MN, Nagai T, Sajjad T, Bheemanathini V, Grewal JS, Paul RV, Raymond JR - " 5-HT(2A) receptors stimulate mitogen-activated protein kinase via H(2)O(2) generation in rat renal mesangial cells" Am J Physiol Renal Physiol 278(4):F650-8 (2000)
https://pubmed.ncbi.nlm.nih.gov/10751227/
Gutkind JS, Offermanns S - "A new G(q)-initiated MAPK signaling pathway in the heart" Dev Cell 16(2):163-4 (2009). doi: 10.1016/j.devcel.2009.01.021."Our studies are most consistent with an ERK activation pathway as follows: 5-HT(2A) receptor --> G(q) protein --> phospholipase C --> diacylglycerol [DAG] --> classical PKC --> NAD(P)H oxidase --> superoxide --> superoxide dismutase [SOD] --> H(2)O(2) --> mitogen-activated extracellular signal-regulated kinase [MAPK] --> ERK."
https://www.cell.com/developmental-cell ... 09)00049-5
"Pathological cardiac hypertrophy involves auto/paracrine mediators acting through G(q/11)-coupled receptors. A novel signaling route stimulated by betagamma-subunits of G(q/11) results in the autophosphorylation of ERK1/2 on a new site and the nuclear retention of ERK1/2, thereby activating hypertrophic gene programs."
Harada T, Horinouchi T, Higa T, Hoshi A, Higashi T, Terada K, Mai Y, Nepal P, Horiguchi M, Hatate C, Miwa S - "Endothelin-1 activates extracellular signal-regulated kinases 1/2 via transactivation of platelet-derived growth factor receptor in rat L6 myoblasts" Life Sci 104(1-2):24-31 (2014). doi: 10.1016/j.lfs.2014.04.002
"These results suggest that ETAR stimulation induces ERK1/2 phosphorylation in L6 myoblasts through Gq/11 protein-dependent, PLC-independent PDGFR transactivation which requires dynamin-dependent ETAR internalization."
Izumi S, Higa-Nakamine S, Nishi H, Torihara H, Uehara A, Sugahara K, Kakinohana M, Yamamoto H - "Phosphorylation of epidermal growth factor receptor at serine 1047 in cultured lung alveolar epithelial cells by bradykinin B2 receptor stimulation" Pulm Pharmacol Ther 48:53-61 (2018)
https://pubmed.ncbi.nlm.nih.gov/28899709/
"Inhibitor studies suggested that Gq/11 was mainly involved in the activation of ERK and p38 MAPK. ....Pharmacological experiments indicated that both ERK and p38 MAPK were involved in the phosphorylation of EGFR."
Lazou A, Sugden PH, Clerk A - "Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart" Biochem J 332 ( Pt 2)(Pt 2):459-65 (1998) doi: 10.1042/bj3320459
https://pubmed.ncbi.nlm.nih.gov/9601075/
"These results indicate that, in addition to the ERKs, two MAPK subfamilies, whose activation is more usually associated with cellular stresses, are activated by the Gq/11-protein-coupled receptor (Gq/11PCR) agonist, PE, in whole hearts. These data indicate that Gq/11PCR agonists activate multiple MAPK signalling pathways in the heart, all of which may contribute to the overall response (e.g. the development of the hypertrophic phenotype)."
Pappa KI, Vlachos GD, Roubelakis M, Vlachos DE, Kalafati TG, Loutradis D, Anagnou NP - "Low mutational burden of eight genes involved in the MAPK/ERK, PI3K/AKT, and GNAQ/11 pathways in female genital tract primary melanomas" Biomed Res Int 2015:303791 (2015). doi: 10.1155/2015/303791
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598382/
Szeto A, Sun-Suslow N, Mendez AJ, Hernandez RI, Wagner KV, McCabe PM - "Regulation of the macrophage oxytocin receptor in response to inflammation" Am J Physiol Endocrinol Metab 312(3):E183-E189 (2017) doi: 10.1152/ajpendo.00346.2016
"OT treatment of control cells and LPS-treated cells increased ERK1/2 phosphorylation, demonstrating activation of the OXTR/Gαq/11 signaling pathway."
https://journals.physiology.org/doi/ful ... 00346.2016
Xu C, Li YM, Sun B, Zhong FJ, Yang LY - "GNA14's interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway" Carcinogenesis 42(11):1357-1369 (2021). doi: 10.1093/carcin/bgab098
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598382/
Thyroid Hormone
Barreiro Arcos ML, Sterle HA, Paulazo MA, Valli E, Klecha AJ, Isse B, Pellizas CG, Farias RN, Cremaschi GA - "Cooperative nongenomic and genomic actions on thyroid hormone mediated-modulation of T cell proliferation involve up-regulation of thyroid hormone receptor and inducible nitric oxide synthase expression" J Cell Physiol 226(12):3208-18 (2011) doi: 10.1002/jcp.22681. PMID: 21344381.
https://onlinelibrary.wiley.com/doi/abs ... /jcp.22681
Incerpi S, Ashur-Fabian O, Davis PJ, Pedersen JZ - "Editorial: Crosstalk between thyroid hormones, analogs and ligands of integrin αvβ3 in health and disease. Who is talking now?" Front Endocrinol (Lausanne) 13:1119952 (2023) doi: 10.3389/fendo.2022.1119952. PMID: 36686434; PMCID: PMC9850369.https://www.frontiersin.org/articles/10 ... 19952/full
"The effect of thyroid hormones is mediated, in part, by activation of PI3-K and ERK1/2 (MAPK). "
Sabatino L - "Nrf2-Mediated Antioxidant Defense and Thyroid Hormone Signaling: A Focus on Cardioprotective Effects" Antioxidants (Basel) 12(6):1177 (2023) doi: 10.3390/antiox12061177
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295725/
"The main intracellular signaling cascade triggered by TH-integrin ανβ3 interaction is the mitogen-activated protein kinase (MAPK; ERK1/2) via phospholipase C (PLC) and protein kinase Cα (PKCα). The TH-activated MAPK mediates the serine phosphorylation of several nuclear trans-activator proteins, such as the signal transducer and activator of transcription 1α and 3 (STAT1α and STAT3), TRβ1, estrogen receptor α (ERα), etc.."
Shih A, Lin HY, Davis FB, Davis PJ - "Thyroid hormone promotes serine phosphorylation of p53 by mitogen-activated protein kinase." Biochemistry. 40(9):2870-8 (2001) doi: 10.1021/bi001978b
https://pubmed.ncbi.nlm.nih.gov/11258898/
Shinderman-Maman E, Cohen K, Weingarten C, Nabriski D, Twito O, Baraf L, Hercbergs A, Davis PJ, Werner H, Ellis M, Ashur-Fabian O - "The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation" Oncogene 35(15):1977-87 (2016) doi: 10.1038/onc.2015.262
https://www.nature.com/articles/onc2015262
DIO3 - Shh
Aw DK, Sinha RA, Tan HC, Loh LM, Salvatore D, Yen PM - "Studies of molecular mechanisms associated with increased deiodinase 3 expression in a case of consumptive hypothyroidism" J Clin Endocrinol Metab. 99(11):3965-71 (2014) doi: 10.1210/jc.2013-3408
https://pubmed.ncbi.nlm.nih.gov/24646062/
"Conclusions: Loss of imprinting did not account for overexpression of DIO3 in the patient's tumor. Instead SHH and MAPK/ERK pathway activation was associated with systemic thyroid hormone catabolism and growth of the tumor. These findings raise the possibility that other tumors that have increased SHH and MAPK/ERK signaling also may have intratumor or systemic effects on thyroid hormone function."
Romitti M, Wajner SM, Ceolin L, Ferreira CV, Ribeiro RV, Rohenkohl HC, Weber Sde S, Lopez PL, Fuziwara CS, Kimura ET, Maia AL - "MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma" Endocr Relat Cancer. 23(3):135-46 (2016). doi: 10.1530/ERC-15-0162.
DIO2Abstract
Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metastatic disease. The objective of this study is to investigate the signaling pathways involved in DIO3 upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples. DIO3 mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein. DIO3 gene silencing was performed via siRNA transfection. DIO3 mRNA levels and activity were readily detected in K1 (BRAF(V6) (0) (0E)) and, at lower levels, in TPC-1 (RET/PTC1) cells (P<0.007 and P=0.02 respectively). Similarly, DIO3 mRNA levels were higher in PTC samples harboring the BRAF(V600E) mutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (P<0.001). Specific inhibition of BRAF oncogene (PLX4032, 3 μM), MEK (U0126, 10-20 μM) or p38 (SB203580, 10-20 μM) signaling was associated with decreases in DIO3 expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 μM) resulted in markedly decreases in DIO3 mRNA levels. Interestingly, siRNA-mediated DIO3 silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels of DIO3 expression in PTC. Importantly, DIO3 silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.
Wang YY, Morimoto S, Du CK, Lu QW, Zhan DY, Tsutsumi T, Ide T, Miwa Y, Takahashi-Yanaga F, Sasaguri T - "Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy" Cardiovasc Res 87(4):636-46 (2010) doi: 10.1093/cvr/cvq133. Epub 2010 May 7. PMID: 20453157.
https://pubmed.ncbi.nlm.nih.gov/20453157/
"Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK."
Fluoride = TSH
Büch TR, Biebermann H, Kalwa H, Pinkenburg O, Hager D, Barth H, Aktories K, Breit A, Gudermann T - "G13-dependent activation of MAPK by thyrotropin" J Biol Chem 283(29):20330-41(2008) doi: 10.1074/jbc.M800211200. Epub 2008 Apr 29. PMID: 18445595
https://pubmed.ncbi.nlm.nih.gov/18445595/
Lyu J, Imachi H, Yoshimoto T, Fukunaga K, Sato S, Ibata T, Kobayashi T, Dong T, Yonezaki K, Yamaji N, Kikuchi F, Iwama H, Ishikawa R, Haba R, Sugiyama Y, Zhang H, Murao K - "Thyroid stimulating hormone stimulates the expression of glucose transporter 2 via its receptor in pancreatic β cell line, INS-1 cells" Sci Rep 8(1):1986 (2018) doi: 10.1038/s41598-018-20449-3. PMID: 29386586; PMCID: PMC5792451
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792451/
Yang C, Lu M, Chen W, He Z, Hou X, Feng M, Zhang H, Bo T, Zhou X, Yu Y, Zhang H, Zhao M, Wang L, Yu C, Gao L, Jiang W, Zhang Q, Zhao J - "Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques" J Exp Med 216(5):1182-1198 (2019) doi: 10.1084/jem.20181473. Epub 2019 Apr 2. PMID: 30940720; PMCID: PMC6504213
https://pubmed.ncbi.nlm.nih.gov/30940720/
"In vitro experiments further revealed that TSH activated MAPKs (ERK1/2, p38α, and JNK) and IκB/p65 pathways in macrophages and increased inflammatory cytokine production and their recruitment of monocytes."