MAPK/ERK信號通路：從基礎生物學到人類疾病的核心樞紐

1. MAPK通路簡介

絲裂原活化蛋白激酶（MAPK）級聯(lián)反應是調(diào)節(jié)多種細胞過程的關鍵信號通路，包括增殖、分化、細胞凋亡和應激反應。MAPK通路通過信號級聯(lián)發(fā)揮作用，將細胞外信號傳遞到細胞內(nèi)靶標，使細胞能夠?qū)Ω鞣N特定的細胞外刺激做出反應。MAPK通路包括三種主要激酶，即MAPK激酶激酶（MAP3K）、MAPK激酶（MAPKK）和MAPK，它們激活和磷酸化下游蛋白質(zhì)。目前的研究發(fā)現(xiàn)有四種主要且不同的MAPK級聯(lián)反應：細胞外信號調(diào)節(jié)激酶1和2（ERK1/2）、c-Jun N端激酶（1、2和3）、p38 MAPK（α、β、γ和δ）和ERK5。本文重點介紹MAPK/ERK信號通路。

1.1 MAPK/ERK通路功能

MAPK/ERK通路是一條至關重要的細胞信號傳導途徑，其核心作用是將細胞外的生長因子信號（如促增殖、分化指令）逐級放大并傳遞至細胞核內(nèi)，通過激活特定的轉(zhuǎn)錄因子來調(diào)控基因表達，從而主導細胞的增殖、分化、存活和代謝等多種關鍵生物學過程。ERK通路中上游蛋白質(zhì)和激酶的過度激活已被證明會誘發(fā)各種疾病，包括癌癥、炎癥、發(fā)育障礙和神經(jīng)系統(tǒng)疾病。此外，MAPK/ERK通路在器官再生過程中具有核心作用。MAPK/ERK信號傳導響應損傷刺激而迅速激活，并協(xié)調(diào)促再生機制，包括細胞存活、遷移、增殖、生長以及相關基因的轉(zhuǎn)錄和翻譯。

1.2 MAPK/ERK通路激活方式

MAPK/ERK通路主要通過配體刺激質(zhì)膜上的受體酪氨酸激酶（RTK）來激活，也可以被G蛋白偶聯(lián)受體（GPCR）激活。然后，RTK信號通過生長因子受體結(jié)合蛋白2（Grb2）和SOS傳遞，激活小GTP酶Ras，招募Ras和Ser/Thr激酶Raf到質(zhì)膜，形成復合物，通過誘導Raf上絲氨酸殘基的磷酸化/去磷酸化來激活Raf?；钚?/span>Raf依次磷酸化并激活MEK1/2。MEK1/2分別對ERK1/2蛋白進行磷酸化從而激活ERK1/2。ERK1/2通過不同亞細胞區(qū)室中的磷酸化激活或滅活多種蛋白質(zhì)，也可以通過磷酸化多個轉(zhuǎn)錄因子靶點，快速穿梭到細胞核中調(diào)節(jié)細胞轉(zhuǎn)錄活性。此外，ERK1/2可以作為負反饋調(diào)控機制，磷酸化ERK通路的上游激酶，如SOS和MEK。

圖1 MAPK/ERK通路調(diào)控機制和功能的簡化示意圖

（圖片源于《Int J Mol Sci》^[1]）

2. MAPK/ERK通路與腫瘤的相關研究

MAPK/ERK通路功能障礙是多種癌癥發(fā)展的主要誘因之一。多項研究發(fā)現(xiàn)MAPK/ERK信號通路的激活可促進結(jié)直腸癌（CRC）^[2]、乳腺癌^[3]、卵巢癌^[4,5]、肝癌^[6]、小細胞肺癌^[7]、甲狀腺癌^[8]、胃癌^[9]等癌癥的發(fā)生、增殖、遷移和侵襲。直接或間接抑制MAPK/ERK信號傳導可抑制腫瘤的增殖和遷移，并減弱惡性表型^[10-12]。MAPK/ERK信號與腫瘤治療耐藥性相關^[13,14]。與這些結(jié)果相反，MAPK/ERK通路是膠質(zhì)母細胞瘤（GB）細胞對抗腫瘤免疫敏感性的關鍵調(diào)節(jié)因子^[15]。GB細胞中實驗誘導的ERK磷酸化提高了免疫檢查點阻斷（ICB）治療的存活率，重新激發(fā)并產(chǎn)生持久的抗腫瘤免疫。此外，多種化合物通過MAPK/ERK通路在腫瘤中發(fā)揮促細胞凋亡作用^[16-18]。這些研究表明MAPK/ERK通路激活是腫瘤進展的一把“雙刃劍”，突出了其在腫瘤治療中的潛在價值。

圖2 PPP2R1B通過MAPK/ERK信號通路促進CRC細胞對奧沙利鉑的敏感性

（圖片源于《Cancer Cell Int》^[14]）

3. MAPK/ERK通路與自身免疫疾病的相關研究

MAPK/ERK在自身免疫性疾病中的作用受到廣泛研究。MAPK/ERK通路介導類風濕性關節(jié)炎成纖維細胞樣滑膜細胞（RA-FLS）的增殖和遷移，并可能有助于RA的進展^[19]。抑制MAPK/ERK信號通路，可減少FLS增殖并減輕RA滑膜炎程度^[20]。精胺通過以MAPK/ERK依賴性方式抑制CD4 T細胞活化和T效應細胞分化來緩解多發(fā)性硬化癥疾病模型進展^[21]。綠原酸可抑制葡聚糖硫酸鈉（DSS）誘導的結(jié)腸炎癥，改善結(jié)腸黏膜中MAPK/ERK通路相關蛋白的表達^[22]。ERK抑制劑逆轉(zhuǎn)了綠原酸對結(jié)腸組織的保護作用。黃芩苷正丁酯通過結(jié)合ERK蛋白和抑制ROS/ERK/P-ERK/NLRP3信號通路抑制細胞焦亡，預防小鼠結(jié)腸炎^[23]。在系統(tǒng)性硬化癥中，IL11依賴性ERK信號傳導介導真皮成纖維細胞激活，促進纖維化表型^[24]。這些結(jié)果表明靶向MAPK/ERK通路可能是一種有前景的自身免疫疾病治療方法。

4. MAPK/ERK通路與心血管疾病

MAPK/ERK信號通路的異常激活廣泛參與心血管疾病的發(fā)生發(fā)展。在壓力超負荷誘導下，ERK1/2磷酸化并激活ETS2，與NFAT形成復合物，驅(qū)動心臟肥大^[25]。抑制MAPK/ERK信號傳導可抑制心肌細胞的進一步肥大^[26]。MAPK/ERK通路表達下調(diào)可預防AngII誘導的小鼠心臟肥大^[27]。研究顯示ERK1/2信號傳導是早期彈性蛋白酶激活的重要調(diào)節(jié)劑，其藥理學抑制可能阻止主動脈瓣疾病（AVD）進展^[28]。穿心蓮內(nèi)酯通過MAPK-ERK信號通路抑制細胞增殖來改善主動脈瓣增生^[29]。磷酸化ERK表達增加對心肌缺血/再灌注損傷具有保護作用，減輕心肌梗死面積，減少心肌細胞細胞凋亡^[30,31]。這些結(jié)果為精準靶向MAPK-ERK來預防和治療心血管疾病提供幫助。

5. MAPK/ERK通路與神經(jīng)退行性疾病

MAPK/ERK通路是神經(jīng)退行性疾病發(fā)展過程中與神經(jīng)炎癥相關的重要通路。研究顯示人參皂苷Rg2對阿爾茨海默?。?/span>AD）的神經(jīng)保護作用可能與MAPK-ERK通路有關^[32]。抑制MAPK/ERK通路可逆轉(zhuǎn)Aβ1-42肽對神經(jīng)干細胞/祖細胞（NSPC）遷移的抑制作用，改善NSPC對AD的治療效果^[33]。帕金森（PD）小鼠模型中抑制MAPK信號傳導可挽救神經(jīng)元細胞死亡和運動功能障礙^[34]。抑制MAPK/ERK途徑可減少LRRK2突變（帕金森病發(fā)病原因之一）細胞系中的異常自噬和細胞凋亡^[35]。MAPK/ERK信號調(diào)節(jié)缺氧誘導的自噬過程，從而改善SOD1突變（肌萎縮側(cè)索硬化癥發(fā)病原因之一）運動神經(jīng)元活力^[36]。因此，探索MAPK信號通路的特異性調(diào)控機制可能為開發(fā)神經(jīng)退行性疾病的新治療藥物提供線索。

圖3 鹽酸托哌酮誘導PD神經(jīng)保護的機制

（圖片源于《Biomed Pharmacother》^[34]）

6. MAPK/ERK通路與再生

越來越多的研究強調(diào)了MAPK/ERK通路在組織和器官再生過程中的重要作用。MAPK/ERK信號通路在電離輻射后的造血重建中發(fā)揮重要作用^[37]。低振幅電場通過激活MAPK/ERK通路調(diào)節(jié)內(nèi)皮血管生成，促進血管組織修復^[38]。適當激活MAPK/ERK信號傳導有助于斑馬魚心臟再生^[39]。MAPK/ERK通路的激活有效促進牙周骨再生，并取得良好的恢復效果^[40]。三七皂苷R1可以促進MAPK/ERK信號通路的激活，下調(diào)TNF-α的表達，最終上調(diào)成骨基因的表達，增強骨再生^[41]。數(shù)據(jù)表明，MAPK/ERK通路調(diào)控肝祖細胞（HPC）的細胞增殖和集落形成，是肝臟再生的關鍵通路^[42]。這些證據(jù)突出了靶向MAPK/ERK通路誘導組織和器官再生能力的可能性和潛力。

圖4 三七皂苷R1促進骨再生

（圖片源于《Front Bioeng Biotechnol》^[41]）

云克隆助力科學研究，為廣大科研人員提供相關檢測試劑產(chǎn)品，相關靶標核心貨號如下：

更多科研試劑，歡迎訪問云克隆官方網(wǎng)站：http://www.19230.cn/

參考文獻

[1]Wen X, Jiao L, Tan H. MAPK/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration. Int J Mol Sci. 2022;23(3):1464.

[2]Bai X, Wei H, Liu W, et al. Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites. Gut. 2022;71(12):2439-2450.

[3]Wu J, Li J, Xu H, Qiu N, Huang X, Li H. Periostin drives extracellular matrix degradation, stemness, and chemoresistance by activating the MAPK/ERK signaling pathway in triple-negative breast cancer cells. Lipids Health Dis. 2023;22(1):153.

[4]Ma H, Qi G, Han F, Gai P, Peng J, Kong B. HMGB3 promotes the malignant phenotypes and stemness of epithelial ovarian cancer through the MAPK/ERK signaling pathway. Cell Commun Signal. 2023;21(1):144.

[5]Chen K, Liu MX, Mak CS, et al. Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Theranostics. 2018;8(2):423-436.

[6]Huang K, Liu Z, Xie Z, et al. HIGD2A silencing impairs hepatocellular carcinoma growth via inhibiting mitochondrial function and the MAPK/ERK pathway. J Transl Med. 2023;21(1):253.

[7]Wang Z, Kan G, Sheng C, Yao C, Mao Y, Chen S. ARHGEF19 regulates MAPK/ERK signaling and promotes the progression of small cell lung cancer. Biochem Biophys Res Commun. 2020;533(4):792-799.

[8]Zhang HM, Li ZY, Dai ZT, et al. Interaction of MRPL9 and GGCT Promotes Cell Proliferation and Migration by Activating the MAPK/ERK Pathway in Papillary Thyroid Cancer. Int J Mol Sci. 2022;23(19):11989.

[9]Ma F, Yao J, Niu X, Zhang J, Shi D, Da M. MARK4 promotes the malignant phenotype of gastric cancer through the MAPK/ERK signaling pathway. Pathol Res Pract. 2024;261:155471.

[10]Hou J, Chen Q, Huang Y, Wu Z, Ma D. Caudatin blocks the proliferation, stemness and glycolysis of non-small cell lung cancer cells through the Raf/MEK/ERK pathway. Pharm Biol. 2022;60(1):764-773.

[11]Zhang H, Liu J, Dang Q, et al. Ribosomal protein RPL5 regulates colon cancer cell proliferation and migration through MAPK/ERK signaling pathway. BMC Mol Cell Biol. 2022;23(1):48.

[12]Li J, Hu S, Zhang Z, Qian L, Xue Q, Qu X. LASP2 is downregulated in human liver cancer and contributes to hepatoblastoma cell malignant phenotypes through MAPK/ERK pathway. Biomed Pharmacother. 2020;127:110154.

[13]Peng WX, Huang JG, Yang L, Gong AH, Mo YY. Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol Cancer. 2017;16(1):161.

[14]Liu W, Tang J, Gao W, Sun J, Liu G, Zhou J. PPP2R1B abolishes colorectal cancer liver metastasis and sensitizes Oxaliplatin by inhibiting MAPK/ERK signaling pathway. Cancer Cell Int. 2024;24(1):90.

[15]Kim KS, Zhang J, Arrieta VA, et al. MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, microglia phenotype, and immune checkpoint blockade efficacy. Preprint. bioRxiv. 2024;2024.09.11.612571.

[16]Jeon SJ, Choi EY, Han EJ, et al. Piperlongumine induces apoptosis via the MAPK pathway and ERK?mediated autophagy in human melanoma cells. Int J Mol Med. 2023;52(6):115.

[17]An J, Li L, Zhang X. Curcusone C induces apoptosis in endometrial cancer cells via mitochondria-dependent apoptotic and ERK pathway. Biotechnol Lett. 2021;43(1):329-338.

[18]Yano S, Wu S, Sakao K, Hou DX. Involvement of ERK1/2-mediated ELK1/CHOP/DR5 pathway in 6-(methylsulfinyl)hexyl isothiocyanate-induced apoptosis of colorectal cancer cells. Biosci Biotechnol Biochem. 2019;83(5):960-969.

[19]Liu F, Feng XX, Zhu SL, et al. Sonic Hedgehog Signaling Pathway Mediates Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via MAPK/ERK Signaling Pathway. Front Immunol. 2018;9:2847.

[20]Chen J, Luo X, Liu M, et al. Silencing long non-coding RNA NEAT1 attenuates rheumatoid arthritis via the MAPK/ERK signalling pathway by downregulating microRNA-129 and microRNA-204. RNA Biol. 2021;18(5):657-668.

[21]Zheng R, Kong M, Wang S, He B, Xie X. Spermine alleviates experimental autoimmune encephalomyelitis via regulating T cell activation and differentiation. Int Immunopharmacol. 2022;107:108702.

[22]Gao W, Wang C, Yu L, et al. Chlorogenic Acid Attenuates Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice through MAPK/ERK/JNK Pathway. Biomed Res Int. 2019;2019:6769789.

[23]Guo M, Wu H, Zhang J, et al. Baicalin n-butyl ester alleviates inflammatory bowel disease and inhibits pyroptosis through the ROS/ERK/P-ERK/NLRP3 pathway in vivo and in vitro. Biomed Pharmacother. 2025;186:118012.

[24]Adami E, Viswanathan S, Widjaja AA, et al. IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGFβ-mediated activation of dermal fibroblasts. Rheumatology (Oxford). 2021;60(12):5820-5826.

[25]Luo Y, Jiang N, May HI, et al. Cooperative Binding of ETS2 and NFAT Links Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy. Circulation. 2021;144(1):34-51.

[26]Ye J, Yan S, Liu R, et al. CMTM3 deficiency induces cardiac hypertrophy by regulating MAPK/ERK signaling. Biochem Biophys Res Commun. 2023;667:162-169.

[27]Hu B, Song JT, Ji XF, Liu ZQ, Cong ML, Liu DX. Sodium Ferulate Protects against Angiotensin II-Induced Cardiac Hypertrophy in Mice by Regulating the MAPK/ERK and JNK Pathways. Biomed Res Int. 2017;2017:3754942.

[28]Munjal C, Jegga AG, Opoka AM, et al. Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model. Physiol Rep. 2017;5(5):e13152.

[29]Huang Y, Liu M, Liu C, Dong N, Chen L. The Natural Product Andrographolide Ameliorates Calcific Aortic Valve Disease by Regulating the Proliferation of Valve Interstitial Cells via the MAPK-ERK Pathway. Front Pharmacol. 2022;13:871748.

[30]Chen Y, Ba L, Huang W, et al. Role of carvacrol in cardioprotection against myocardial ischemia/reperfusion injury in rats through activation of MAPK/ERK and Akt/eNOS signaling pathways. Eur J Pharmacol. 2017;796:90-100.

[31]Fu C, Wang M, Lu Y, et al. Polygonum orientale L. Alleviates Myocardial Ischemia-Induced Injury via Activation of MAPK/ERK Signaling Pathway. Molecules. 2023;28(9):3687.

[32]Ye X, Shao S, Wang Y, Su W. Ginsenoside Rg2 alleviates neurovascular damage in 3xTg-AD mice with Alzheimer's disease through the MAPK-ERK pathway. J Chem Neuroanat. 2023;133:102346.

[33]Wang Z, Chen Y, Li X, Sultana P, Yin M, Wang Z. Amyloid-β1-42 dynamically regulates the migration of neural stem/progenitor cells via MAPK-ERK pathway. Chem Biol Interact. 2019;298:96-103.

[34]Zaman B, Mostafa I, Hassan T, et al. Tolperisone hydrochloride improves motor functions in Parkinson's disease via MMP-9 inhibition and by downregulating p38 MAPK and ERK1/2 signaling cascade. Biomed Pharmacother. 2024;174:116438.

[35]Bravo-San Pedro JM, Niso-Santano M, Gómez-Sánchez R, et al. The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci. 2013;70(1):121-136.

[36]D'Amico AG, Maugeri G, Saccone S, et al. PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2020;21(8):2943.

[37]Yang L, Lu Y, Zhang Z, et al. Oxymatrine boosts hematopoietic regeneration by modulating MAPK/ERK phosphorylation after irradiation-induced hematopoietic injury. Exp Cell Res. 2023;427(2):113603.

[38]Sheikh AQ, Taghian T, Hemingway B, Cho H, Kogan AB, Narmoneva DA. Regulation of endothelial MAPK/ERK signalling and capillary morphogenesis by low-amplitude electric field. J R Soc Interface. 2013;10(78):20120548.

[39]Liu P, Zhong TP. MAPK/ERK signalling is required for zebrafish cardiac regeneration. Biotechnol Lett. 2017;39(7):1069-1077.

[40]Chen H, Liu N, Hu S, et al. Yeast β-glucan-based nanoparticles loading methotrexate promotes osteogenesis of hDPSCs and periodontal bone regeneration under the inflammatory microenvironment. Carbohydr Polym. 2024;342:122401.

[41]Liu Y, Zhang Y, Zheng Z, et al. Incorporation of NGR1 promotes bone regeneration of injectable HA/nHAp hydrogels by anti-inflammation regulation via a MAPK/ERK signaling pathway. Front Bioeng Biotechnol. 2022;10:992961.

[42]Jin C, Samuelson L, Cui CB, Sun Y, Gerber DA. MAPK/ERK and Wnt/β-Catenin pathways are synergistically involved in proliferation of Sca-1 positive hepatic progenitor cells. Biochem Biophys Res Commun. 2011;409(4):803-807.