ERK/MAPK signalling pathway and tumorigenesis

Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.

[1]  J. Blenis,et al.  The RSK family of kinases: emerging roles in cellular signalling , 2008, Nature Reviews Molecular Cell Biology.

[2]  D. Morrison,et al.  Regulation of MAP kinase signaling modules by scaffold proteins in mammals. , 2003, Annual review of cell and developmental biology.

[3]  Michiyuki Matsuda,et al.  Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging , 2019, Cancers.

[4]  Yoo Jin Jung,et al.  The transcriptional landscape and mutational profile of lung adenocarcinoma , 2012, Genome research.

[5]  J. Lundeberg,et al.  NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing , 2006, Melanoma research.

[6]  Honglin Luo,et al.  Molecular Cloning of Mouse ERK5/BMK1 Splice Variants and Characterization of ERK5 Functional Domains* , 2001, The Journal of Biological Chemistry.

[7]  Frank McCormick,et al.  RAS Proteins and Their Regulators in Human Disease , 2017, Cell.

[8]  Yuan Xu,et al.  SPARCL1 suppresses the proliferation and migration of human ovarian cancer cells via the MEK/ERK signaling. , 2018, Experimental and therapeutic medicine.

[9]  D. Morrison,et al.  Ras-Mediated Activation of the Raf Family Kinases. , 2019, Cold Spring Harbor perspectives in medicine.

[10]  K. Patterson,et al.  Dual-specificity phosphatases: critical regulators with diverse cellular targets. , 2009, The Biochemical journal.

[11]  C. Der,et al.  The role of wild type RAS isoforms in cancer. , 2016, Seminars in cell & developmental biology.

[12]  Steffen Hauptmann,et al.  Expression of mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) in primary human ovarian carcinoma , 2002, International journal of cancer.

[13]  E. Goldsmith,et al.  Phosphorylation of the MAP Kinase ERK2 Promotes Its Homodimerization and Nuclear Translocation , 1998, Cell.

[14]  M. Javan,et al.  New Insights Into Implementation of Mesenchymal Stem Cells in Cancer Therapy: Prospects for Anti-angiogenesis Treatment , 2019, Front. Oncol..

[15]  Roger J. Davis,et al.  TNF and MAP kinase signalling pathways. , 2014, Seminars in immunology.

[16]  H. Dohlman,et al.  Regulation of large and small G proteins by ubiquitination , 2019, The Journal of Biological Chemistry.

[17]  J. Ramos,et al.  RSK isoforms in cancer cell invasion and metastasis. , 2013, Cancer research.

[18]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[19]  I. Berindan‐Neagoe,et al.  A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer , 2019, Cancers.

[20]  Chunli Shao,et al.  The roles of MAPKs in disease , 2008, Cell Research.

[21]  F. Dehghani,et al.  The Cytoskeleton—A Complex Interacting Meshwork , 2019, Cells.

[22]  E. Nishida,et al.  Regulation of Nuclear Translocation of Extracellular Signal-Regulated Kinase 5 by Active Nuclear Import and Export Mechanisms , 2006, Molecular and Cellular Biology.

[23]  R. Seger,et al.  The ERK signaling cascade—Views from different subcellular compartments , 2009, BioFactors.

[24]  P. LoRusso,et al.  Clinical experience of MEK inhibitors in cancer therapy. , 2007, Biochimica et biophysica acta.

[25]  R. Seger,et al.  Protein-protein interactions in the regulation of the extracellular signal-regulated kinase , 2005, Molecular biotechnology.

[26]  C. Flaitz,et al.  PD 098059, an inhibitor of ERK1 activation, attenuates the in vivo invasiveness of head and neck squamous cell carcinoma , 1999, British Journal of Cancer.

[27]  P. Crespo,et al.  Protein-Protein Interactions: Emerging Oncotargets in the RAS-ERK Pathway. , 2018, Trends in cancer.

[28]  Y. Ho,et al.  Vascular Endothelial Growth Factor-C Upregulates Cortactin and Promotes Metastasis of Esophageal Squamous Cell Carcinoma , 2014, Annals of Surgical Oncology.

[29]  X. F. Zhang,et al.  Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. , 2001, Recent progress in hormone research.

[30]  M. Nikiforova,et al.  Molecular and Histopathologic Characteristics of Multifocal Papillary Thyroid Carcinoma , 2013, The American journal of surgical pathology.

[31]  Nancy Y. Ip,et al.  ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF , 1991, Cell.

[32]  Jing Zhao,et al.  Role of big mitogen-activated protein kinase 1 (BMK1) / extracellular signal-regulated kinase 5 (ERK5) in the pathogenesis and progression of atherosclerosis. , 2012, Journal of pharmacological sciences.

[33]  Jingwu Xie,et al.  MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas , 2009, Cell cycle.

[34]  W. Park,et al.  Colorectal tumors frequently express phosphorylated mitogen‐activated protein kinase , 2004, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[35]  P. Leung,et al.  Gonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cells , 2000, Molecular and Cellular Endocrinology.

[36]  Myungsun Shin,et al.  Isoform-selective activity-based profiling of ERK signaling† †Electronic supplementary information (ESI) available: Experimental Methods and Supplementary Figures. See DOI: 10.1039/c8sc00043c , 2018, Chemical science.

[37]  H. Namba,et al.  Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. , 2003, The Journal of clinical endocrinology and metabolism.

[38]  Steven J. M. Jones,et al.  Oncogenic Signaling Pathways in The Cancer Genome Atlas. , 2018, Cell.

[39]  Wei-Wei Pan,et al.  DAXX promotes ovarian cancer ascites cell proliferation and migration by activating the ERK signaling pathway , 2018, Journal of Ovarian Research.

[40]  A. Schulze,et al.  Analysis of the transcriptional program induced by Raf in epithelial cells , 2001, Nature Genetics.

[41]  F. McCormick,et al.  Activation of c‐Raf‐1 by Ras and Src through different mechanisms: activation in vivo and in vitro , 1997, The EMBO journal.

[42]  R. Roskoski Targeting ERK1/2 protein-serine/threonine kinases in human cancers. , 2019, Pharmacological research.

[43]  Jesse S. Voss,et al.  Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  B. Su,et al.  Dimerization through the Catalytic Domain Is Essential for MEKK2 Activation* , 2005, Journal of Biological Chemistry.

[45]  S. Pileri,et al.  BRAF mutations in hairy-cell leukemia. , 2011, The New England journal of medicine.

[46]  M. Heikenwalder,et al.  The role of polarisation of circulating tumour cells in cancer metastasis , 2019, Cellular and Molecular Life Sciences.

[47]  I. Nagtegaal,et al.  BRAF mutation in metastatic colorectal cancer. , 2009, The New England journal of medicine.

[48]  R. Seger,et al.  The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. , 2011, Biochimica et biophysica acta.

[49]  Y. Bang,et al.  Increased MAPK activity and MKP-1 overexpression in human gastric adenocarcinoma. , 1998, Biochemical and biophysical research communications.

[50]  Klaus Pantel,et al.  Liquid Biopsy: Current Status and Future Perspectives , 2017, Oncology Research and Treatment.

[51]  S. T. Eblen Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes. , 2018, Advances in cancer research.

[52]  W. Kolch Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. , 2000, The Biochemical journal.

[53]  Donghui Wang,et al.  Angiotensin II type 2 receptor–interacting protein 3a inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated ERK/EMT pathway , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[54]  E. Gelfand,et al.  MEKK2 Associates with the Adapter Protein Lad/RIBP and Regulates the MEK5-BMK1/ERK5 Pathway* , 2001, The Journal of Biological Chemistry.

[55]  Guohua Liu,et al.  Targeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinoma. , 2017, Oncology letters.

[56]  E. Nishida,et al.  Activation of a C-terminal Transcriptional Activation Domain of ERK5 by Autophosphorylation* , 2007, Journal of Biological Chemistry.

[57]  Y. Zou,et al.  miR‑101 regulates the cell proliferation and apoptosis in diffuse large B‑cell lymphoma by targeting MEK1 via regulation of the ERK/MAPK signaling pathway. , 2018, Oncology reports.

[58]  San-Duk Yang,et al.  Aberrant epigenetic regulation of GABRP associates with aggressive phenotype of ovarian cancer , 2017, Experimental &Molecular Medicine.

[59]  C. Gialeli,et al.  Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting , 2011, The FEBS journal.

[60]  Qing-Yu He,et al.  RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma , 2019, Cancers.

[61]  B. Jiang,et al.  P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression. , 2010, Biochemical and biophysical research communications.

[62]  P. Ladenson,et al.  Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. , 2013, JAMA.

[63]  S. Keyse,et al.  Dual-specificity MAP kinase phosphatases in health and disease☆ , 2019, Biochimica et biophysica acta. Molecular cell research.

[64]  T. Miyase,et al.  Association of suppression of extracellular signal-regulated kinase phosphorylation by epigallocatechin gallate with the reduction of matrix metalloproteinase activities in human fibrosarcoma HT1080 cells. , 2003, Journal of agricultural and food chemistry.

[65]  B. Evers,et al.  Alterations of MAPK activities associated with intestinal cell differentiation. , 2001, Biochemical and biophysical research communications.

[66]  A. Flanagan,et al.  In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low‐grade serous tumours , 2004, The Journal of pathology.

[67]  Hao Xu,et al.  Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways. , 2007, Chinese medical journal.

[68]  Frank McCormick,et al.  Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond , 2014, Nature Reviews Cancer.

[69]  L. Martiny,et al.  The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells. , 2005, Experimental cell research.

[70]  D. Bell,et al.  Origins and molecular pathology of ovarian cancer , 2005, Modern Pathology.

[71]  O. Kozawa,et al.  Involvement of p38 MAP kinase in TGF‐β‐stimulated VEGF synthesis in aortic smooth muscle cells , 2001, Journal of cellular biochemistry.

[72]  Ton Wang,et al.  BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers , 2018, Drugs.

[73]  P. Jänne,et al.  Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non–Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial , 2017, JAMA.

[74]  Rony Seger,et al.  The MEK/ERK cascade: from signaling specificity to diverse functions. , 2007, Biochimica et biophysica acta.

[75]  G. Botti,et al.  BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  A. Ullrich,et al.  The Unique C-terminal Tail of the Mitogen-activated Protein Kinase ERK5 Regulates Its Activation and Nuclear Shuttling* , 2005, Journal of Biological Chemistry.

[77]  J C Reed,et al.  Human intestinal epithelial cell survival: differentiation state-specific control mechanisms. , 2001, American journal of physiology. Cell physiology.

[78]  R. Roskoski ERK1/2 MAP kinases: structure, function, and regulation. , 2012, Pharmacological research.

[79]  Oleksii S. Rukhlenko,et al.  Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. , 2018, Cell systems.

[80]  D. Herr,et al.  G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. , 2017, Biochimica et biophysica acta. Molecular cell research.

[81]  R. Seger,et al.  Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer , 2019, International journal of molecular sciences.

[82]  W. Kolch,et al.  Conferring specificity on the ubiquitous Raf/MEK signalling pathway , 2004, British Journal of Cancer.

[83]  T. Ganesan,et al.  Tumour angiogenesis—Origin of blood vessels , 2016, International journal of cancer.

[84]  Su-qing Yang,et al.  Long Noncoding RNA MIR4697HG Promotes Cell Growth and Metastasis in Human Ovarian Cancer , 2017, Analytical cellular pathology.

[85]  Satoko Nishimoto,et al.  MAPK signalling: ERK5 versus ERK1/2 , 2006, EMBO reports.

[86]  S. Roy,et al.  FGF9‐induced ovarian cancer cell invasion involves VEGF‐A/VEGFR2 augmentation by virtue of ETS1 upregulation and metabolic reprogramming , 2018, Journal of cellular biochemistry.

[87]  Han-Wei Lin,et al.  Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. , 2012, The Biochemical journal.

[88]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[89]  Masahito Watanabe,et al.  Proliferative effects of γ‐aminobutyric acid on the gastric cancer cell line are associated with extracellular signal‐regulated kinase 1/2 activation , 2009, Journal of gastroenterology and hepatology.

[90]  Alan R. Saltiel,et al.  Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo , 1999, Nature Medicine.

[91]  Rony Seger,et al.  The ERK Cascade: Distinct Functions within Various Subcellular Organelles. , 2011, Genes & cancer.

[92]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[93]  Zhong Yao and Rony Seger The Molecular Mechanism of MAPK / ERK Inactivation , 2004 .

[94]  M. Bogoyevitch,et al.  c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. , 2010, Biochimica et biophysica acta.

[95]  R. Seger,et al.  The dynamic subcellular localization of ERK: mechanisms of translocation and role in various organelles. , 2016, Current opinion in cell biology.

[96]  David L. Brautigan,et al.  The Specificity of Extracellular Signal-regulated Kinase 2 Dephosphorylation by Protein Phosphatases* , 2002, The Journal of Biological Chemistry.

[97]  E. Wagner,et al.  Signal integration by JNK and p38 MAPK pathways in cancer development , 2009, Nature Reviews Cancer.

[98]  Qing-Yu He,et al.  RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma , 2019, Cancers.

[99]  J. Kuriyan,et al.  The Interdependent Activation of Son-of-Sevenless and Ras. , 2019, Cold Spring Harbor Perspectives in Medicine.

[100]  J. Pouysségur,et al.  Total ERK1/2 activity regulates cell proliferation , 2009, Cell cycle.

[101]  M. Ladanyi,et al.  Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  Min Song,et al.  Mechanistic insight into activation of MAPK signaling by pro-angiogenic factors , 2018, BMC Systems Biology.

[103]  Rony Seger,et al.  The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. , 2010, Methods in molecular biology.

[104]  K. Ji,et al.  Ras and Rap1: A tale of two GTPases. , 2019, Seminars in cancer biology.

[105]  Jieun Park,et al.  Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases. , 2011, Toxicology.

[106]  W. Kolch,et al.  Regulation of the MAPK pathway by raf kinase inhibitory protein. , 2014, Critical reviews in oncogenesis.

[107]  I. Shih,et al.  Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. , 2003, Journal of the National Cancer Institute.

[108]  Herb Chen,et al.  ZM336372, A Raf-1 Activator, Causes Suppression of Proliferation in a Human Hepatocellular Carcinoma Cell Line , 2008, Journal of Gastrointestinal Surgery.

[109]  L. Hong,et al.  MicroRNA‐508 suppresses epithelial‐mesenchymal transition, migration, and invasion of ovarian cancer cells through the MAPK1/ERK signaling pathway , 2018, Journal of cellular biochemistry.

[110]  F. Zheng,et al.  Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer , 2017, Cellular Physiology and Biochemistry.

[111]  F. Meric-Bernstam,et al.  Targeting TRK family proteins in cancer , 2017, Pharmacology & therapeutics.

[112]  Y. Li,et al.  Sp1-CD147 positive feedback loop promotes the invasion ability of ovarian cancer. , 2015, Oncology reports.

[113]  Y. Zimmer,et al.  A Comparative Analysis of Individual RAS Mutations in Cancer Biology , 2019, Front. Oncol..

[114]  R. Roskoski,et al.  RAF protein-serine/threonine kinases: structure and regulation. , 2010, Biochemical and biophysical research communications.

[115]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[116]  Jeanne Shen,et al.  Clinical, Pathologic, and Biologic Features Associated with BRAF Mutations in Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[117]  R. Tapping,et al.  MEKK3 Directly Regulates MEK5 Activity as Part of the Big Mitogen-activated Protein Kinase 1 (BMK1) Signaling Pathway* , 1999, The Journal of Biological Chemistry.

[118]  A. Nebreda,et al.  Roles of p38α mitogen‐activated protein kinase in mouse models of inflammatory diseases and cancer , 2015, The FEBS journal.

[119]  H. Chung,et al.  Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis , 2000, Oncogene.

[120]  W. Kolch Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[121]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[122]  C. V. Jongeneel,et al.  Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma , 2011, Nature Genetics.

[123]  M. Raffeld,et al.  Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. , 2012, Blood.