ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos 10.3892/etm.2020.8454 ETM-0-0-8454 Review ERK/MAPK signalling pathway and tumorigenesis GuoYan-Jun PanWei-Wei LiuSheng-Bing ShenZhong-Fei XuYing HuLing-Ling Department of Human Anatomy and Embryology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China Correspondence to: Professor Yan-Jun Guo, Department of Human Anatomy and Embryology, College of Medicine, Jiaxing University, 118 Jiahang Road, Jiaxing, Zhejiang 314001, P.R. China, E-mail: yanjun_guo@163.com 03 2020 15 01 2020 19 3 1997 2007 03072019 04122019 Copyright: © Guo et al. 2020 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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.

 extracellular signal-regulated kinase Ras Raf ERK mitogen-activated protein kinase pathway tumorigenesis cancer Introduction

Extracellular signal-regulated kinase 1/2 (ERK) belongs to the mitogen-activated protein kinase (MAPK) family, which plays a role in signalling cascades and transmits extracellular signals to intracellular targets. Therefore, MAPK cascades are central signalling elements that regulate basic processes including cell proliferation, differentiation and stress responses (1–3). These cascades transmit signals through sequential activation of three to five layers of protein kinases known as MAPK kinase kinase kinase (MAP4K), MAPK kinase kinase (MAP3K), MAPK kinase (MAPKK), MAPK and MAPK-activated protein kinases (MAPKAPK). The first three central layers are considered as a basic core unit, while the last two layers appear in some cascades and can vary among cells and stimuli. Four MAPK cascades have been defined based on the components in the MAPK layer: ERK1/2, c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5. This review focuses on the ERK cascade (4–6) which involves several kinases in the MAP3K layer (mainly Rafs), including Ras/Raf/MAPK (MEK) 1/2 at the MAPKK layer, ERK1/2 at the MAPK layer and several MAPKAPKs in the next layer (ribosomal s6 kinases, MAP kinase-interacting serine/threonine-protein kinases, mitogen- and stress-activated protein kinases and cytosolic phospholipase A2). ERK cascades are highly regulated cascades that are responsible for basic cellular processes, including cell proliferation and differentiation. These regulatory factors affect bispecific phosphatases (7–10), scaffold proteins (11–14), signal duration and intensity (15), and the dynamic subcellular localization of cascade components (16,17). Due to the importance of the ERK cascade, ERK disorders are harmful to cells and ultimately to the body. Excessive activation of upstream proteins and kinases in the ERK pathway has been shown to induce various diseases, including cancer, inflammation, developmental disorders and neurological disorders (18–22). Since ERK1 and ERK2 are very similar, the singular form of ERK is used in this review, although two subtypes exist.

Dysfunction in the Ras-ERK pathway is a major trigger for the development of most cancer types (23). Activation of the ERK cascade occurs in most cancer types, whereby activating mutations of this pathway are the most abundant oncogenic factor across all cancer types (24). Different components in the cascade are highly variable in human cancers (24). Driver mutations in ras (mainly K-ras) are the most common mutations in cancer, appearing in ~30% of all cancer types (25) and in ~10% of all patients with cancer (26). raf mutations (particularly in B-raf) have been detected in ~8% of all cancer types (26). The frequency of extracellular signal-regulated kinase kinase (MEK) mutations is low (~1%), though a few major pathogenic mutations in ERK have been reported (26,27). This review focuses on the mechanism of the nuclear ERK/MAPK signalling pathway in cancer development. Specifically, the basic components of the MAPK signalling pathway and its basic structure, function and ERK composition are summarized. The role of ERK in tumour proliferation and invasion-metastasis is also reviewed, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised, which has important therapeutic significance for preventing ERK/MAPK gene mutation.

 MAPK signalling pathways

Among the numerous intracellular signalling pathways, the MAPK pathway plays a more important role in cell proliferation, differentiation, apoptosis, angiogenesis and tumour metastasis than other pathways. The following four MAPK cascades have been identified in eukaryotic cells: ERK, JNK/stress-activated protein kinase, p38 MAPK and ERK5 signal transduction pathways. Each MAPK signalling cascade consists of at least three tiers: MAP3K, MAPKK and MAPK (3,6) (Fig. 1). Studies have shown that the JNK and p38 MAPK pathways are mainly related to stress and apoptosis of cells, while the ERK/MAPK signalling pathway, which is the most thoroughly studied MAPK signalling pathway, is closely related to cell proliferation and differentiation and plays a pivotal role in the cell signal transduction network (11,28–30).

 ERK/MAPK structure and functions

Among all the signalling networks, the MAPK signal transmission pathway plays an important role in controlling various physiological processes in cells, such as cell growth, development, division and death. ERK is a member of the MAPK family, and the ERK/MAPK signalling pathway is the core of the signalling network involved in regulating cell growth, development and division. The basic signal transmission steps follow the MAPK tertiary enzymatic cascade, consisting of an upstream activator sequence, MAP3K, MAP2K and MAPK. In the ERK pathway, Ras acts as an upstream activating protein, Raf acts as MAP3K, MAPK/ERK kinase (MEK) acts as MAPKK and ERK is the MAPK, forming the Ras-Raf-MEK-ERK pathway (31).

<sec> <title>Members of the ERK family

ERK, a type of serine/threonine protein kinase, is a signal transduction protein that transmits mitogen signals (32). ERK is generally located in the cytoplasm; upon activation, ERK enters the nucleus and regulates transcription factor activity and gene expression (33). Through artificial cloning and sequencing analysis, the ERK family has been shown to consist of ERK 1, 2, 3, 5 and 6 (3). ERK1 and ERK2 are two important members of the MAPK/ERK pathway, with molecular weights of 44 and 42 kDa, respectively (33). The C-terminus of ERK5 contains a nuclear localization signal (NLS), two proline-rich regions and a transcriptional activation domain (TAD). ERK5 is more than twice the molecular weight of other MAPKs (110 kDa). This structural difference enables active ERK5 to self-phosphorylate its C-terminal TAD, which is a unique ability of ERK5 to directly control its own gene transcription (34). In the non-phosphorylated state, ERK5 is in an inactive conformation and its N- and C-terminal domains are interconnected in the cytoplasm. Activation of MEK5 induces open conformation of ERK5, exposes the NLS, alleviates self-inhibition and promotes ERK5 translocation to the nucleus (35–37). ERK5 activity is also regulated by its splicing variants (a, b, and c) (38). Only ERK5a shows kinase activity, and both ERK5b and c are deficient in protein kinase activity and can inhibit MEK5-mediated ERK5a stimulation. The current manuscript focuses on the ERK1/2/MAPK signalling pathway.

 ERK pathway upstream protein and kinase activation mechanism

Multiple stimulants such as growth factors, cytokines, viruses, G-protein-coupled receptor ligands and oncogenes activate the ERK pathway. Key molecules in the ERK/MAPK signalling pathway mainly include the small G proteins Ras and downstream Raf kinase, MEK1/2 and ERK1/2. Ras is the most conserved product encoded by the Ha-ras, Hi-ras and N-ras oncogenes of the ras gene family. Raf kinase is a product of the raf oncogene. MEK1 and MEK2 are rare dual-specificity kinases that can activate ERK through phosphorylation at two regulatory sites, Tyr 204/187 and Thr 202/185 (30).

 Ras

Ras, an upstream protein of the Raf-MEK-ERK pathway, was the earliest discovered small G protein and product of the ras oncogene (39). It has an active GTP-binding conformation and an inactive GDP-binding conformation (40). The protein can alternate between the two conformations to regulate signal transduction (41). Ras is activated by many stimulating factors, such as epidermal growth factor (EGF), tumour necrosis factor, activators of protein kinase C (PKC) and Src family members (42). When an extracellular signal binds to the receptor, a connector molecule, growth factor receptor-binding protein 2 (Grb2), binds to the activated receptor and interacts with the proline-rich sequence at the C-terminus of son of sevenless (SOS) to form the receptor-Grb2-SOS complex. Binding of SOS to the Tyr phosphorylation site on the receptor or receptor substrate protein leads to translocation of cytoplasmic SOS to the membrane, resulting in a high concentration of SOS near Ras (43). SOS and Ras-GDP promote the replacement of GDP with GTP in Ras, thereby activating Ras to initiate the Ras pathway (44) (Fig. 2).

 Raf

The Raf protein kinase is a protein encoded by the raf gene and is composed of 648 amino acids (aa) with a molecular weight of 40–75 kDa (42). Raf exhibits serine/threonine protein kinase activity after binding to Ras. Its molecular structure comprises three conserved regions: Conserved region (CR) l (located at aa 61–194), CR2 (located at aa 254–269) and CR3 (located at aa 335–627). CRl, located at the amino terminus, is rich in cysteine and contains a zinc finger-like structure, similar to the ligand-binding region of PKC (45). CR1 is the main site of activated Ras binding to Raf-1 protein kinase. CR2 is present near the amino terminus and contains many serine and threonine residues (45). CR3, located at the carboxyl terminus, is the catalytic functional region of the Raf-1 protein kinase (46). The Raf kinase family has three subtypes: Raf-1, A-Raf and B-Raf. Raf kinases can be activated in the following ways: i) Localisation of Raf on the inside of the cell membrane through its interaction with Ras (47); ii) dimerization of Raf protein; iii) phosphorylation and dephosphorylation at different sites; iv) dissociation with Raf kinase inhibitor protein; and v) binding to Ras kinase inhibitor (47). Raf-1 plays an important role in the Ras/Raf/MEK/ERK cell proliferation signalling pathway. Stokoe et al (48) suggested that activation of Raf-1 occurs in two steps. The first step is Ras binding to and fixing Raf-1 on the inner side of the membrane; the second step is activation of Raf-1, which may be conducted by tyrosine kinase. In the Ras/Raf/MEK/ERK proliferation signal transduction pathway, Ras, as the upstream activated protein, uses two regions, the Ras-binding domain and cysteine-rich domain at the N-terminus of Raf-1, to bind and translocate Raf from the cytoplasm to the cell membrane, where Raf is activated. Activated Raf-1 continues to activate downstream MEK and MAPK, and finally delivers cell proliferation and differentiation signals to the nucleus by regulating the activity of various transcriptional regulators, which regulate gene expression (49). Although Raf kinases are highly conserved among subtypes, their activity, tissue distribution and modality of regulation differ (50). A-Raf shows the weakest kinase activity, while B-Raf shows the strongest activity. Among the three subtypes, B-Raf has the highest mutation rate, which is 90% in melanoma (Table I) (51–73).

 MEK (MAPK/ERK kinase)

When Raf is activated, its C-terminal catalytic domain can interact with MEK, and its catalytic VIII subregion is phosphorylated at the serine residue, activating MEK. The two MEK subtypes, MEK1 and MEK2, have molecular weights of 44 and 45 kDa, respectively (74). MEK is a rare dual-specificity kinase that activates ERK by phosphorylating the Tyr and Thr regulatory sites (75). How MEK has both Tyr and Thr specific phosphorylation activity is unclear, but it has important physiological significance, as the ERK signalling pathway is in a central position in the cell signal transduction network, and any errors in activation can profoundly influence cellular processes. This recognition and activation mechanism that confers double specificity greatly improves the accuracy of signal transduction and prevents errors in ERK activation (62).

 ERK

MAPK/ERK is a Ser/Thr protein kinase. When multiple kinases act on MEK, activated MEK directly interacts with ERKs through its N-terminal region, catalysing the bispecific phosphorylation of Tyr and Thr residues in the 8 ‘TEY box’ of the sub-functional region of ERK to activate ERK. MEK not only activates ERK, but also anchors ERK in the cytoplasm. When the signalling pathway is inactive, ERK is localized to the cytoplasm. Once a signal stimulates the phosphorylation and dimerization of ERK, activated ERKs are translocated to the nucleus, promote cytoplasmic target protein phosphorylation or regulate the activity of other protein kinases, followed by further phosphorylation of downstream substrates. Avruch et al (76) studied the process of ERK2 phosphorylation and translocation into the nucleus and found that both phosphorylated and unphosphorylated ERK2 form a homologous dimer before nuclear translocation, indicating that formation of the homologous dimer is necessary for ERK nuclear translocation (25,47).

 Activation of the ERK/MAPK signalling pathway

Various stimulating factors, such as cytokines, viruses, G-protein-coupled receptor ligands and oncogenes, play regulatory roles by activating the ERK/MAPK signalling pathway. The ERK/MAPK signalling pathway can be activated through the following ways: i) Ca2+activation; ii) receptor tyrosine kinase Ras activation; iii) PKC-mediated activation; and iv) G protein-coupled receptor activation (77).

 Downstream of ERK1/2

ERK1/2 is located in the cytoplasm of unstimulated cells. Once activated, ERK1/2 is transferred to the nucleus and regulates the activity of various transcription factors through phosphorylation, eventually regulating cell metabolism and function and influencing the specific biological effects of cells (Fig. 3). Cytoskeletal components such as microtubule-associated protein (MAP) 1, MAP2 and MAP4 are phosphorylated in the cytoplasm to participate in the regulation of cell morphology and cytoskeletal redistribution. In the nucleus, the phosphorylation of nuclear transcription factors such as proto-oncogene c-Fos, proto-oncogene c-Jun, ETS domain-containing protein Elk-1, proto-oncogene c-Myc and cyclic AMP-dependent transcription factor ATF2. Cytoplasmic ERK1/2 can phosphorylate a series of other protein kinases upstream of the ERK pathway, such as SOS, Raf-1 and MEK in a negative feedback regulatory manner (Fig. 4). Activation of ERK/MAPK signalling pathways activates other extracellular signalling pathways. Extracellular signals such as vascular endothelial growth factor (VEGF), platelet-derived growth factor and EGF can be activated by receptor tyrosine kinase autologous phosphorylation of the ERK/MAPK signalling pathway. Activated ERK may enter the nucleus and bind to transcription factors that induce gene expression in response to extracellular stimuli, and regulate cell proliferation, differentiation, apoptosis and transcription (4,80–83).

<sec> <label>6.</label> <title>ERK/MAPK signalling pathway and tumorigenesis

The ERK/MAPK signalling pathway is not only involved in regulating cellular biological functions, such as cell proliferation, cell differentiation, cell cycle regulation, cell apoptosis and tissue formation, but is also related to tumour formation (84) (Fig. 5). Elevated ERK expression has been detected in various human tumours, such as ovarian, colon, breast and lung cancer (85–88). Denkert et al (89) found that the expression of MAPK phosphatase-1 (MKP-1) in normal ovarian surface epithelium and benign cystadenomas is increased compared to invasive carcinomas and low malignancy potential tumors and borderline tumors. The expression level of MKP-1 in tumour tissues of patients with stage III/IV disease was significantly lower compared with that in patients with stage I/II disease. Expression of the phosphorylated form of ERK1/2 (p-ERK1/2) was significantly increased in normal ovarian tissues, benign tumours and borderline tumours. The expression level of p-ERK1/2 in stage III/IV patients was significantly higher compared with that in stage I/II patients. There was a significant negative correlation between MKP-1 and p-ERK1/2 expression in the same ovarian cancer tissue detected by immunohistochemistry and western blotting. Abnormal expression of MKP-1 and ERKs may play a role in the development of ovarian cancer. Hong et al (90) found that the expression levels of MAPK1 and ERK in ovarian cancer tissues were higher compared with those in adjacent normal tissues. Lee et al (91) showed that the rates of MEK phosphorylation in colon cancer, villous adenoma and tubular adenoma were 76, 40 and 30%, respectively, while the phosphorylation of MEK in normal colonic mucosal cells was barely detectable. Continuous activation of the ERK/MAPK signalling pathway can promote the transformation of normal cells into tumour cells, while inhibition of the ERK/MAPK signalling pathway can restore tumour cells to a non-transformed state in vitro and can inhibit tumour growth in vivo (92). Therefore, increased activation of the ERK/MAPK signalling pathway may be closely related to the occurrence and development of tumours.

 Role of ERK/MAPK in cell proliferation

Unlimited cell proliferation, dedifferentiation and a lack of apoptosis are important biological characteristics of tumours (93). The activation of the ERK/MAPK signalling pathway promotes proliferation and has an anti-apoptotic effect. Hypoxia-induced VEGF can inhibit the apoptosis of serum-starved cells by activating the ERK/MAPK signalling pathway (94). Inhibiting the expression of this pathway can inhibit the proliferation of and lack of apoptosis in tumour cells, and promote their differentiation (95). Gauthier et al (96) found that the ERK1/2 signalling pathway is involved in cell survival following intestinal injury, and inhibition of this pathway can promote the apoptosis of intestinal injury cells. Huang et al (97) found that blocking the ERK/MAPK signalling pathway inhibited the proliferation of a diffuse large B cell lymphoma cell line and promoted cell apoptosis. Inhibiting the expression of the ERK/MAPK signalling pathway to inhibit tumour cell proliferation may involve inhibition of the cell cycle (98). Sebolt-Leopold et al (92) showed that the use of MEK1/2 inhibitors to inhibit ERK1/2 activity in colon cancer cells could prevent the cells from entering the S phase from the G1 phase, and inhibit the growth of adherent cells. Inhibition of the ERK/MAPK signalling pathway can reduce cell dedifferentiation and the anti-apoptosis effect. Maemura et al (99) reported that the ERK/MAPK signalling pathway promotes proliferation and inhibits apoptosis by influencing the activity of downstream cell cycle regulatory proteins, apoptosis-related proteins and other effector molecules, such as G1/S specific cyclin D1. Ellipticine, an alkaloid with anti-tumour activity, induces apoptosis of the human endometrial cancer cell line RL95-2 by activating reactive oxygen species and MAPK/ERK (18). Gonadotropin-releasing hormone induces activation of the MAPK signaling pathway in normal and carcinoma cells of the human ovary and placenta (100). SPACRC-like protein 1 (SPARCL1) is overexpressed in ovarian cancer; by inhibiting activation of the MEK/ERK signalling pathway, SPARCL1 is downregulated through the MEK/ERK pathway and inhibits the proliferation and migration of ovarian cancer cells (101).

 ERK/MAPK signalling in tumour invasion and metastasis

Invasion and metastasis of tumour cells occurs in three stages: Adhesion, degradation and migration. Tumour cells break away from the primary tumour, adhere to the basement membrane and become invasive. Tumour cells infiltrate and grow in the surrounding stroma and enter the circulatory system, where most cells are killed by the immune system. A small number of tumour cells with strong survival ability reach the target organ and continue to proliferate, forming new metastases in the same manner as the primary tumour. This process involves the coordination of multiple signalling pathways, and the ERK/MAPK signalling pathway plays an important role in tumour invasion and metastasis (102).

Sung et al (103) established a mouse model of metastatic xenotransplantation using human ovarian carcinoma SK-OV-3 cells. They found that γ-aminobutyric acid receptor subunit π (GABRP) expression was upregulated (>4-fold) in metastatic tissues from the xenograft mice compared with SK-OV-3 cells. GABRP knockdown diminished the migration and invasion of SK-OV-3 cells and reduced ERK activation, while overexpression of GABRP exhibited significantly increased cell migration, invasion and ERK activation. The MEK inhibitor U0126 is a specific and non-ATP-competitive MEK1 and MEK2 inhibitor. U0126 acts on recombinant constitution-activated mutant MEK1 (at sites DN3-S218E/S222D), blocking MAPK signal transmission. U0126 inhibited the migration and invasion of SK-OV-3 cells (103). Liu et al (104) found that death domain-associated protein 6 promoted the proliferation and migration of ovarian cancer ascites cells by activating the ERK signalling pathway. Zhao et al (105) found that CD147 promoted Sp1 phosphorylation at T453 and T739 through the PI3K/AKT and MAPK/ERK pathways and that blocking the positive feedback loop of Sp1-CD147 reduced the invasive ability of human ovarian cancer (ho8910) cells. The Sp1-CD147 positive feedback loop may play a key role in the invasive ability of ovarian cancer cells. Down-regulation of the long non-coding RNA MIR4697 host gene (MIR4697HG) promotes the growth and metastasis of ovarian cancer cells by lowering levels of matrix metalloproteinase-9, p-ERK, and phosphorylated AKT (106). Downregulation of MIR4697HG inhibited cell migration and invasion (106).

 ERK/MAPK signalling pathway is involved in degradation of the tumour extracellular matrix

Matrix metalloproteinases (MMPs) are proteolytic enzymes that hydrolyse the extracellular matrix (ECM), which is one of the most important processes in the invasion and metastasis of cancer cells (107). Overexpression of MMPs is beneficial for tumour invasion and metastasis, while inhibiting the expression of MMPs has the opposite effects. Maeda-Yamamoto et al (108) showed that inhibition of ERK phosphorylation by epigallocatechin gallate in fibrosarcoma HT1080 cells resulted in inhibition of MMP-2 and MMP-9 expression in these cells. The expression of MMP-2 and MMP-9 depends on the phosphorylation of ERK. Simon et al (109) found that in oral cancer cells, ERK1/ERK2 activation inhibitors reduced the activity of ERK1/ERK2 while downregulating MMP-9 and reducing invasiveness. The activation of the ERK/MAPK signalling pathway can increase tumour invasion and metastasis by upregulating MMP expression, while inhibition of this signalling pathway can reduce tumour invasion and metastasis (110–111). A previous study reported that mesothelin regulates the expression of MMP-7 through the MAPK/ERK signal transduction pathway, ERK1/2, AKT and JNK pathways, which enhances the invasiveness of ovarian cancer (112). In vitro, an ERK1/2 inhibitor or decoy activator protein 1 oligonucleotide inhibited MMP-7 expression and the migration of MSLN-treated ovarian cancer cells. Intra-tumoural MMP-7 expression was reduced by a kinase/ERK inhibitor, resulting in delayed tumour growth and prolonged survival of mice (113).

 ERK/MAPK signalling pathway is involved in tumour cell migration

Cell deformation and migration occurs during tumour metastasis. The expression of cytoskeletal and microfilament-related proteins is related to the deformation and migration of tumour cells. The human colon cancer cell line SW620 showed a larger number of intracellular microfilaments and a longer migration distance upon treatment with hepatocyte growth factor (HGF) compared with a control treatment. The study showed that HGF enhanced cell migration by activating the ERK/MAPK signalling pathway, thus promoting the invasion and metastasis of tumour cells. Further studies showed that protein phosphorylation is associated with regulation of the microfilament cytoskeleton (114–115). Bray et al (114) demonstrated that ERK/MAPK signalling pathways transduce extracellular signals and regulate the expression of transcription factors that cause cytoskeleton deformation and enhance tumour invasion and metastasis. Blocking the ERK/MAPK signalling pathway may inhibit the role of HGF and other extracellular signals that promote cell movement, which inhibits tumour invasion and metastasis.

 Role of activation of ERK/MAPK signalling pathway in tumour angiogenesis

All processes in cells, including tumour cells, require certain nutrients, which are provided to cells through blood vessels. In the absence of blood vessels, tumour tissues rarely exceed 2 mm3 (116); blood vessels are also the channels through which tumour metastasis occurs (117). Tumour angiogenesis involves not only the overexpression of angiogenic factors, but also the low expression of angiogenic inhibitors and an imbalance between the two (118). VEGF is an important pro-angiogenic factor and the most powerful pro-vascular endothelial growth cytokine that promotes cell division and vascular construction from esophageal cancer and ovarian cancer, increases microvascular permeability and promotes endothelial cell migration (119–121).

ERK/MAPK signalling pathways can activate transcription factors to enhance the transcription of VEGF, increasing VEGF expression in tumour cells and promoting the formation of blood vessels. The MAPK/ERK pathway can inhibit thrombospondin-1, the expression of which promotes blood vessel formation and thus promotes tumour growth, invasion and metastasis. Interleukin (IL)-8 and VEGF are jointly expressed in various tumours and can promote tumour angiogenesis, growth and metastasis. ERK1/2 can be used as an alternative pathway to induce the expression of IL-8 and VEGF, thereby promoting the formation of tumour blood vessels. Inhibition of the ERK/MAPK signalling pathway provides a theoretical basis for inhibiting tumour angiogenesis, thereby inhibiting tumour growth and metastasis. Soula-Rothhut et al (122) showed that the MEK inhibitor U0126 inhibited the expression of thrombospondin-1 induced by follicular thyroid carcinoma-133. Activation of the ERK/MAPK signalling pathway plays a role in inducing VEGF expression in colorectal cancer (123). HGF upregulates the expression of VEGF in colorectal cancer cells through the MEK/MAPK or PI3K/AKT signalling pathways (124). Inhibition of MEK/MAPK and PI3K/AKT signalling pathways can reduce VEGF expression, inhibit tumour angiogenesis and inhibit tumour growth and metastasis.

The downstream target of ERK/MAPK, the 70-kDa ribosomal S6 kinase 1 (p70S6K1), is an important regulator of cell cycle progression and proliferation. A study showed that vector-based small interfering RNA against p70S6K1 inhibited p70S6K1 activity in ovarian cancer cells and decreased VEGF protein expression (124). Downregulation of p70S6K1 inhibits the growth and angiogenesis of ovarian tumours and reduces the proliferation and expression levels of VEGF and hypoxia-inducible factor-1α in tumour tissues, further inhibiting the growth and angiogenesis of ovarian tumours (125).

 Conclusions

This review summarized how the ERK/MAPK signalling pathway affects the occurrence and development of human tumours. Further studies will reveal additional details regarding the role of MAPK signalling pathways in tumour pathogenesis. The cellular signalling pathway is a complex network. Activation of a signalling molecule by its downstream signal has biological effects such as promoting or inhibiting tumour cell growth and invasion; however, the regulatory mechanism of synergism or antagonism among intracellular signalling pathways remains unclear. The role of signalling pathways in cellular processes requires further analysis to clarify the role of signalling pathways in tumorigenesis and development. This may further provide new methods for treating tumours.

 Acknowledgements

Not applicable.

 Funding

This study was supported by The Natural Science Foundation of Zhejiang Province (grant no. LY17H160060), the National Natural Science Foundation of China (grant nos. 31871402 and 81402162), the Experimental Animal Science and Technology Plan Projects of Zhejiang Province (grant no. 2017C37173) and the College Student's Science and Technology Innovation Project (grant no. 2018R417024).

 Availability of data and materials

Not applicable.

 Authors' contributions

YJG, WWP and SBL conceived and designed the article. YX and ZFS analysed the relevant literature. YJG wrote the manuscript and drew the figures. YJG, YX, ZFS and LLH made revised the manuscript. YJG, WWP and SBL are responsible for text layout.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

 References KeshetYSegerRThe MAP kinase signaling cascades: A system of hundreds of components regulates a diverse array of physiological functionsMethods Mol Biol661338201010.1007/978-1-60761-795-2_120811974 SabioGDavisRJTNF and MAP kinase signalling pathwaysSemin Immunol26237245201410.1016/j.smim.2014.02.00924647229 PlotnikovAZehoraiEProcacciaSSegerRThe MAPK cascades: Signaling components, nuclear roles and mechanisms of nuclear translocationBiochim Biophys Acta181316191633201110.1016/j.bbamcr.2010.12.01221167873 EblenSTExtracellular-regulated kinases: Signaling from ras to ERK substrates to control biological outcomesAdv Cancer Res13899142201810.1016/bs.acr.2018.02.00429551131 RoskoskiRJrERK1/2 MAP kinases: Structure, function, and regulationPharmacol Res66105143201210.1016/j.phrs.2012.04.00522569528 WortzelISegerRThe ERK cascade: Distinct functions within various subcellular organellesGenes Cancer2195209201110.1177/194760191140732821779493 SeternesOMKidgerAMKeyseSMDual-specificity MAP kinase phosphatases in health and diseaseBiochim Biophys Acta Mol Cell Res1866124143201910.1016/j.bbamcr.2018.09.00230401534 PattersonKIBrummerTO'BrienPMDalyRJDual-specificity phosphatases: Critical regulators with diverse cellular targetsBiochem J418475489200910.1042/BJ2008223419228121 ZhouBWangZXZhaoYBrautiganDLZhangZYThe specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatasesJ Biol Chem2773181831825200210.1074/jbc.M20037720012082107 YaoZSegerRThe molecular mechanism of MAPK/ERK inactivationCurr Genomics5385393200410.2174/1389202043349309 KolchWCoordinating ERK/MAPK signalling through scaffolds and inhibitorsNat Rev Mol Cell Biol6827837200510.1038/nrm174316227978 MorrisonDKDavisRJRegulation of MAP kinase signaling modules by scaffold proteins in mammalsAnnu Rev Cell Dev Biol1991118200310.1146/annurev.cellbio.19.111401.09194214570565 ChuderlandDSegerRProtein-protein interactions in the regulation of the extracellular signal-regulated kinaseMol Biotechnol295774200510.1385/MB:29:1:5715668520 ShaulYDSegerRThe MEK/ERK cascade: From signaling specificity to diverse functionsBiochim Biophys Acta177312131226200710.1016/j.bbamcr.2006.10.00517112607 MarshallCJSpecificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activationCell80179185199510.1016/0092-8674(95)90401-87834738 WainsteinESegerRThe dynamic subcellular localization of ERK: Mechanisms of translocation and role in various organellesCurr Opin Cell Biol391520201610.1016/j.ceb.2016.01.00726827288 YaoZSegerRThe ERK signaling cascade-views from different subcellular compartmentsBiofactors35407416200910.1002/biof.5219565474 KimJYLeeSGChungJYKimYJParkJEKohHHanMSParkYCYooYHKimJMEllipticine induces apoptosis in human endometrial cancer cells: The potential involvement of reactive oxygen species and mitogen-activated protein kinasesToxicology28991102201110.1016/j.tox.2011.07.01421843585 YoshizumiMKyotaniYZhaoJNagayamaKItoSTsujiYOzawaKRole of big mitogen-activated protein kinase 1 (BMK1)/extracellular signal-regulated kinase 5 (ERK5) in the pathogenesis and progression of atherosclerosisJ Pharmacol Sci120259263201210.1254/jphs.12R11CP23165802 BogoyevitchMANgoeiKRZhaoTTYeapYYNgDCc-Jun N-terminal kinase (JNK) signaling: Recent advances and challengesBiochim Biophys Acta1804463475201010.1016/j.bbapap.2009.11.00219900593 WagnerEFNebredaARSignal integration by JNK and p38 MAPK pathways in cancer developmentNat Rev Cancer9537549200910.1038/nrc269419629069 GuptaJNebredaARRoles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancerFEBS J28218411857201510.1111/febs.1325025728574 García-GómezRBusteloXRCrespoPProtein-protein interactions: Emerging oncotargets in the RAS-ERK pathwayTrends Cancer4616633201810.1016/j.trecan.2018.07.00230149880 KhotskayaYBHollaVRFaragoAFMills ShawKRMeric-BernstamFHongDSTargeting TRK family proteins in cancerPharmacol Ther1735866201710.1016/j.pharmthera.2017.02.00628174090 Maik-RachlineGHacohen-Lev-RanASegerRNuclear ERK: Mechanism of translocation, substrates, and role in cancerInt J Mol Sci20piiE1194201910.3390/ijms2005119430857244 Sanchez-VegaFMinaMArmeniaJChatilaWKLunaALaKCDimitriadoySLiuDLKanthetiHSSaghafiniaSOncogenic signaling pathways in the cancer genome atlasCell173321337.e10201810.1016/j.cell.2018.03.03529625050 HolderfieldMDeukerMMMcCormickFMcMahonMTargeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyondNat Rev Cancer14455467201410.1038/nrc376024957944 KyriakisJMAvruchJMammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammationPhysiol Rev81807869200110.1152/physrev.2001.81.2.80711274345 KhokhlatchevAVCanagarajahBWilsbacherJRobinsonMAtkinsonMGoldsmithECobbMHPhosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocationCell93605615199810.1016/S0092-8674(00)81189-79604935 ChangLKarinMMammalian MAP kinase signalling cascadesNature4103740200110.1038/3506500011242034 YangSLiuGTargeting the Ras/Raf/MEK/ERK pathway in hepatocellular carcinomaOncol Lett1310411047201710.3892/ol.2017.555728454211 AnjumRBlenisJThe RSK family of kinases: Emerging roles in cellular signallingNat Rev Mol Cell Biol9747758200810.1038/nrm250918813292 BoultonTGNyeSHRobbinsDJIpNYRadziejewskaEMorgenbesserSDDePinhoRAPanayotatosNCobbMHYancopoulosGDERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGFCell65663675199110.1016/0092-8674(91)90098-J2032290 MorimotoHKondohKNishimotoSTerasawaKNishidaEActivation of a C-terminal transcriptional activation domain of ERK5 by autophosphorylationJ Biol Chem2823544935456200710.1074/jbc.M70407920017928297 BuschbeckMUllrichAThe unique C-terminal tail of the mitogen-activated protein kinase ERK5 regulates its activation and nuclear shuttlingJ Biol Chem28026592667200510.1074/jbc.M41259920015548525 NishimotoSNishidaEMAPK signalling: ERK5 versus ERK1/2EMBO Rep7782786200610.1038/sj.embor.740075516880823 KondohKTerasawaKMorimotoHNishidaERegulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanismsMol Cell Biol2616791690200610.1128/MCB.26.5.1679-1690.200616478989 YanCLuoHLeeJDAbeJBerkBCMolecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domainsJ Biol Chem2761087010878200110.1074/jbc.M00928620011139578 ZhouBDerCJCoxADThe role of wild type RAS isoforms in cancerSemin Cell Dev Biol586069201610.1016/j.semcdb.2016.07.01227422332 Muñoz-MaldonadoCZimmerYMedováMA comparative analysis of individual RAS mutations in cancer biologyFront Oncol91088201910.3389/fonc.2019.0108831681616 DohlmanHGCampbellSLRegulation of large and small G proteins by ubiquitinationJ Biol Chem2941861318623201910.1074/jbc.REV119.01106831645437 TerrellEMMorrisonDKRas-mediated activation of the raf family kinasesCold Spring Harb Perspect Med9piia033746201910.1101/cshperspect.a03374629358316 BandaruPKondoYKuriyanJThe interdependent activation of son-of-sevenless and rasCold Spring Harb Perspect Med9piia031534201910.1101/cshperspect.a03153429610148 SimanshuDKNissleyDVMcCormickFRAS proteins and their regulators in human diseaseCell1701733201710.1016/j.cell.2017.06.00928666118 RukhlenkoOSKhorsandFKrsticARozancJAlexopoulosLGRauchNEricksonKEHlavacekWSPosnerRGGómez-CocaSDissecting RAF inhibitor resistance by structure-based modeling reveals ways to overcome oncogenic RAS signalingCell Syst7161179.e14201810.1016/j.cels.2018.06.00230007540 RoskoskiRJrRAF protein-serine/threonine kinases: Structure and regulationBiochem Biophys Res Commun399313317201010.1016/j.bbrc.2010.07.09220674547 RoskoskiRJrTargeting ERK1/2 protein-serine/threonine kinases in human cancersPharmacol Res142151168201910.1016/j.phrs.2019.01.03930794926 StokoeDMcCormickFActivation of c-Raf-1 by Ras and Src through different mechanisms: Activation in vivo and in vitroEMBO J1623842396199710.1093/emboj/16.9.23849171352 VandammeDHerreroAAl-MullaFKolchWRegulation of the MAPK pathway by raf kinase inhibitory proteinCrit Rev Oncog19405415201410.1615/CritRevOncog.201401192225597351 DingQWangQEversBMAlterations of MAPK activities associated with intestinal cell differentiationBiochem Biophys Res Commun284282288200110.1006/bbrc.2001.496911394874 ColombinoMCaponeMLissiaACossuARubinoCDe GiorgiVMassiDFonsattiEStaibanoSNappiOBRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanomaJ Clin Oncol3025222529201210.1200/JCO.2011.41.245222614978 Edlundh-RoseEEgyháziSOmholtKMånsson-BrahmeEPlatzAHanssonJLundebergJNRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: A study based on mutation screening by pyrosequencingMelanoma Res16471478200610.1097/01.cmr.0000232300.22032.8617119447 NambaHNakashimaMHayashiTHayashidaNMaedaSRogounovitchTIOhtsuruASaenkoVAKanematsuTYamashitaSClinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancersJ Clin Endocrinol Metab8843934397200310.1210/jc.2003-03030512970315 DaviesHBignellGRCoxCStephensPEdkinsSCleggSTeagueJWoffendinHGarnettMJBottomleyWMutations of the BRAF gene in human cancerNat417949954200210.1038/nature00766 MuruganAKDongJXieJXingMMEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomasCell Cycle821222124200910.4161/cc.8.13.871019411838 NikolaevSIRimoldiDIseliCValsesiaARobyrDGehrigCHarshmanKGuipponiMBukachOZoeteVExome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanomaNat Genet44133139201110.1038/ng.102622197931 WangDBoernerSAWinklerJDLoRussoPMClinical experience of MEK inhibitors in cancer therapyBiochim Biophys Acta177312481255200710.1016/j.bbamcr.2006.11.00917194493 JännePAvan den HeuvelMMBarlesiFCoboMMazieresJCrinòLOrlovSBlackhallFWolfJGarridoPSelumetinib 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 trialJAMA31718441853201710.1001/jama.2017.343828492898 SeoJSJuYSLeeWCShinJYLeeJKBleazardTLeeJJungYJKimJOShinJYThe transcriptional landscape and mutational profile of lung adenocarcinomaGenome Res2221092119201210.1101/gr.145144.11222975805 CardarellaSOginoANishinoMButaneyMShenJLydonCYeapBYShollLMJohnsonBEJännePAClinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancerClin Cancer Res1945324540201310.1158/1078-0432.CCR-13-065723833300 TolJNagtegaalIDPuntCJBRAF mutation in metastatic colorectal cancerN Engl J Med3619899200910.1056/NEJMc090416019571295 JonesJCRenfroLAAl-ShamsiHOSchrockABRankinAZhangBYKasiPMVossJSLealADSunJNon-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancerJ Clin Oncol3526242630201710.1200/JCO.2016.71.439428486044 SiebenNLMacropoulosPRoemenGMKolkman-UljeeSMJan FleurenGHoumadiRDissTWarrenBAl AdnaniMDe GoeijAPIn ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumoursJ Pathol202336340200410.1002/path.152114991899 BellDAOrigins and molecular pathology of ovarian cancerMod Pathol18(Suppl 2)S19S32200510.1038/modpathol.380030615761464 SingerGOldtRIIICohenYWangBGSidranskyDKurmanRJShihIeMMutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinomaJ Natl Cancer Inst95484486200310.1093/jnci/95.6.48412644542 BansalMGandhiMFerrisRLNikiforovaMNYipLCartySENikiforovYEMolecular and histopathologic characteristics of multifocal papillary thyroid carcinomaAm J Surg Pathol3715861591201310.1097/PAS.0b013e318292b78023797723 PaikPKArcilaMEFaraMSimaCSMillerVAKrisMGLadanyiMRielyGJClinical characteristics of patients with lung adenocarcinomas harboring BRAF mutationsJ Clin Oncol2920462051201110.1200/JCO.2010.33.128021483012 XingMAlzahraniASCarsonKAViolaDEliseiRBendlovaBYipLMianCVianelloFTuttleRMAssociation between BRAF V600E mutation and mortality in patients with papillary thyroid cancerJAMA30914931501201310.1001/jama.2013.319023571588 TiacciETrifonovVSchiavoniGHolmesAKernWMartelliMPPucciariniABigernaBPaciniRWellsVABRAF mutations in hairy-cell leukemiaN Engl J Med36423052315201110.1056/NEJMoa101420921663470 XiLAronsENavarroWCalvoKRStetler-StevensonMRaffeldMKreitmanRJBoth variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutationBlood11933303332201210.1182/blood-2011-09-37933922210875 ChaoTHHayashiMTappingRIKatoYLeeJDMEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathwayJ Biol Chem2743603536038199910.1074/jbc.274.51.3603510593883 ChengJYuLZhangDHuangQSpencerDSuBDimerization through the catalytic domain is essential for MEKK2 activationJ Biol Chem2801347713482200510.1074/jbc.M41425820015695508 SunWKesavanKSchaeferBCGarringtonTPWareMJohnsonNLGelfandEWJohnsonGLMEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathwayJ Biol Chem27650935100200110.1074/jbc.M00371920011073940 ManningGWhyteDBMartinezRHunterTSudarsanamSThe protein kinase complement of the human genomeScience29819121934200210.1126/science.107576212471243 MutaYMatsudaMImajoMDivergent dynamics and functions of ERK MAP kinase signaling in development, homeostasis and cancer: Lessons from fluorescent bioimagingCancers (Basel)11piiE513201910.3390/cancers1104051330974867 AvruchJKhokhlatchevAKyriakisJMLuoZTzivionGVavvasDZhangXFRas activation of the Raf kinase: Tyrosine kinase recruitment of the MAP kinase cascadeRecent Prog Horm Res56127155200110.1210/rp.56.1.12711237210 LawrenceMCJivanAShaoCDuanLGoadDZaganjorEOsborneJMcGlynnKStippecSEarnestSThe roles of MAPKs in diseaseCell Res18436442200810.1038/cr.2008.3718347614 ShinMFranksCEHsuKLIsoform-selective activity-based profiling of ERK signalingChem Sci924192431201810.1039/C8SC00043C29732117 SanchezJNWangTCohenMSBRAF and MEK inhibitors: Use and resistance in BRAF-mutated cancersDrugs78549566201810.1007/s40265-018-0884-829488071 KolchWMeaningful relationships: The regulation of the Ras/Raf/MEK/ERK pathway by protein interactionsBiochem J351289305200010.1042/0264-6021:351028911023813 SchulzeALehmannKJefferiesHBMcMahonMDownwardJAnalysis of the transcriptional program induced by Raf in epithelial cellsGenes Dev15981994200110.1101/gad.19110111316792 DemingDGeigerPChenHVaccaroAKunnimalaiyaanMHolenKZM336372, a Raf-1 activator, causes suppression of proliferation in a human hepatocellular carcinoma cell lineJ Gastrointest Surg12852857200810.1007/s11605-008-0495-x18299943 O'NeillEKolchWConferring specificity on the ubiquitous Raf/MEK signalling pathwayBr J Cancer90283288200410.1038/sj.bjc.660148814735164 RubinfeldHSegerRThe ERK cascade: A prototype of MAPK signalingMol Biotechnol31151174200510.1385/MB:31:2:15116170216 BhartiyaDSinghJFSH-FSHR3-stem cells in ovary surface epithelium: Basis for adult ovarian biology, failure, aging, and cancerReproduction149R35E48201510.1530/REP-14-022025269615 BangYJKwonJHKangSHKimJWYangYCIncreased MAPK activity and MKP-1 overexpression in human gastric adenocarcinomaBiochem Biophys Res Commun2504347199810.1006/bbrc.1998.92569735328 RaoAHerrDRG protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cellsBiochim Biophys Acta Mol Cell Res186413181327201710.1016/j.bbamcr.2017.05.00128476646 TangQWuJZhengFHannSSChenYEmodin increases expression of insulin-like growth factor binding protein 1 through activation of MEK/ERK/AMPKα and interaction of PPARγ and Sp1 in lung cancerCell Physiol Biochem41339357201710.1159/00045628128214826 DenkertCSchmittWDBergerSRelesAPestSSiegertALichteneggerWDietelMHauptmannSExpression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinomaInt J Cancer102507513200210.1002/ijc.1074612432554 HongLWangYChenWYangSMicroRNA-508 suppresses epithelial-mesenchymal transition, migration, and invasion of ovarian cancer cells through the MAPK1/ERK signaling pathwayJ Cell Biochem11974317440201810.1002/jcb.2705229781537 LeeSHLeeJWSoungYHKimSYNamSWParkWSKimSHYooNJLeeJYColorectal tumors frequently express phosphorylated mitogen-activated protein kinaseAPMIS112233238200410.1111/j.1600-0463.2004.apm11204-0502.x15233637 Sebolt-LeopoldJSDudleyDTHerreraRVan BecelaereKWilandAGowanRCTecleHBarrettSDBridgesAPrzybranowskiSBlockade of the MAP kinase pathway suppresses growth of colon tumors in vivoNat Med5810816199910.1038/1053310395327 MaderSPantelKLiquid biopsy: Current status and future perspectivesOncol Res Treat40404408201710.1159/00047801828693023 BaekJHJangJEKangCMChungHYKimNDKimKWHypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosisOncogene1946214631200010.1038/sj.onc.120381411030151 LeflochRPouysségurJLenormandPTotal ERK1/2 activity regulates cell proliferationCell cycle8705711200910.4161/cc.8.5.773419242111 GauthierRHarnoisCDroletJFReedJCVézinaAVachonPHHuman intestinal epithelial cell survival: Differentiation state-specific control mechanismsAm J Physiol Cell Physiol280C1540C1554200110.1152/ajpcell.2001.280.6.C154011350749 HuangYZouYLinLMaXZhengRmiR-101 regulates the cell proliferation and apoptosis in diffuse large B-cell lymphoma by targeting MEK1 via regulation of the ERK/MAPK signaling pathwayOncol Rep41377386201930365139 ShahSBrockEJJiKMattinglyRRRas and Rap1: A tale of two GTPasesSemin Cancer Biol542939201910.1016/j.semcancer.2018.03.00529621614 MaemuraKShiraishiNSakagamiKKawakamiKInoueTMuranoMWatanabeMOtsukiYProliferative effects of gamma-aminobutyric acid on the gastric cancer cell line are associated with extracellular signal-regulated kinase 1/2 activationJ Gastroenterol Hepatol24688696200910.1111/j.1440-1746.2008.05687.x19032445 KangSKTaiCJChengKWLeungPCGonadotropin-releasing hormone activates mitogen-activated protein kinase in human ovarian and placental cellsMol Cell Endocrinol170143151200010.1016/S0303-7207(00)00320-811162898 MaYXuYLiLSPARCL1 suppresses the proliferation and migration of human ovarian cancer cells via the MEK/ERK signalingExp Ther Med1631953201201830233672 SulzmaierFJRamosJWRSK isoforms in cancer cell invasion and metastasisCancer Res7360996105201310.1158/0008-5472.CAN-13-108724097826 SungHYYangSDJuWAhnJHAberrant epigenetic regulation of GABRP associates with aggressive phenotype of ovarian cancerExp Mol Med49e335201710.1038/emm.2017.6228524180 LiuSBLinXPXuYShenZFPanWWDAXX promotes ovarian cancer ascites cell proliferation and migration by activating the ERK signaling pathwayJ Ovarian Res1190201810.1186/s13048-018-0462-430336783 ZhaoJYeWWuJLiuLYangLGaoLChenBZhangFYangHLiYSp1-CD147 positive feedback loop promotes the invasion ability of ovarian cancerOncol Rep346776201510.3892/or.2015.399925998266 ZhangLQYangSQWangYFangQChenXJLuHSZhaoLPLong noncoding RNA MIR4697HG promotes cell growth and metastasis in human ovarian cancerAnal Cell Pathol (Amst)20178267863201728168162 GialeliCTheocharisADKaramanosNKRoles of matrix metalloproteinases in cancer progression and their pharmacological targetingFEBS J2781627201110.1111/j.1742-4658.2010.07919.x21087457 Maeda-YamamotoMSuzukiNSawaiYMiyaseTSanoMHashimoto-OhtaAIsemuraMAssociation of suppression of extracellular signal-regulated kinase phosphorylation by epigallocatechin gallate with the reduction of matrix metalloproteinase activities in human fibrosarcoma HT1080 cellsJ Agric Food Chem5118581863200310.1021/jf021039l12643642 SimonCHicksMJNemechekAJMehtaRO'MalleyBWJrGoepfertHFlaitzCMBoydDPD 098059, an inhibitor of ERK1 activation, attenuates the in vivo invasiveness of head and neck squamous cell carcinomaBr J Cancer8014121419199910.1038/sj.bjc.669053710424744 BraicuCBuseMBusuiocCDrulaRGuleiDRadulyLRusuAIrimieAAtanasovAGSlabyOA comprehensive review on MAPK: A promising therapeutic target in cancerCancers (Basel)11piiE1618201910.3390/cancers1110161831652660 GaoJWangYYangJZhangWMengKSunYLiYHeQYRNF128 promotes invasion and metastasis via the EGFR/MAPK/MMP-2 pathway in esophageal squamous cell carcinomaCancers (Basel)11piiE840201910.3390/cancers1106084031216681 ChangMCChenCAChenPJChiangYCChenYLMaoTLLinHWLin ChiangWHChengWFMesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathwaysBiochem J442293302201210.1042/BJ2011028221999204 HohmannTDehghaniFThe cytoskeleton-A complex interacting meshworkCells8piiE362201910.3390/cells804036231003495 BrayDCell movements, 2nd editionnGarland PublishingNew York792001 YamamotoTKozawaOTanabeKAkamatsuSMatsunoHDohiSUematsuTInvolvement of p38 MAP kinase in TGF-beta-stimulated VEGF synthesis in aortic smooth muscle cellsJ Cell Biochem82591598200110.1002/jcb.117911500937 Krishna PriyaSNagareRPSnehaVSSidhanthCBindhyaSManasaPGanesanTSTumour angiogenesis-Origin of blood vesselsInt J Cancer139729735201610.1002/ijc.3006726934471 HeikenwalderMLorentzenAThe role of polarisation of circulating tumour cells in cancer metastasisCell Mol Life Sci7637653781201910.1007/s00018-019-03169-331218452 JavanMRKhosrojerdiAMoazzeniSMNew insights into implementation of mesenchymal stem cells in cancer therapy: Prospects for anti-angiogenesis treatmentFront Oncol9840201910.3389/fonc.2019.0084031555593 SongMFinleySDMechanistic insight into activation of MAPK signaling by pro-angiogenic factorsBMC Syst Biol12145201810.1186/s12918-018-0668-530591051 SuCMSuYHChiuCFChangYWHongCCYuYHHoYSWuCHYenCSSuJLVascular endothelial growth factor-C upregulates cortactin and promotes metastasis of esophageal squamous cell carcinomaAnn Surg Oncol21(Suppl 4)S767S775201410.1245/s10434-014-4009-725212831 BhattacharyaRRay ChaudhuriSRoySSFGF9-induced ovarian cancer cell invasion involves VEGF-A/VEGFR2 augmentation by virtue of ETS1 upregulation and metabolic reprogrammingJ Cell Biochem11981748189201810.1002/jcb.2682029904943 Soula-RothhutMCoissardCSarteletHBoudotCBellonGMartinyLRothhutBThe tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cellsExp Cell Res304187201200510.1016/j.yexcr.2004.10.02615707585 ZhangYHWeiWXuHWangYYWuWXInducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathwaysChin Med J (Engl)120743748200710.1097/00029330-200705010-0000217531111 BianCXShiZMengQJiangYLiuLZJiangBHP70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expressionBiochem Biophys Res Commun398395399201010.1016/j.bbrc.2010.06.08020599538 PingHGuoLXiJWangDAngiotensin II type 2 receptor-interacting protein 3a inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated ERK/EMT pathwayTumor Biol3910104283177133892017

MAPK cascades. MAPKs, which are present in the cytoplasm and can be translocated into the nucleus, catalyse the phosphorylation of dozens of cytosolic proteins and numerous nuclear transcription factors. Adapted from (29). MAPK, mitogen-activated protein kinase; MAP4K, MAPK kinase kinase kinase; MAP3K, MAPK kinase kinase; MAPKK, MAPK kinase; MAPKAPK, mitogen-activated protein kinase-activated protein kinases; MEK, Ras/Raf/MAPK; RSK, ribosomal s6 kinase; MSK, mitogen- and stress-activated protein kinases; MNK, MAP kinase-interacting serine/threonine-protein kinases; cPLA2, cytosolic phospholipase A2; c-FOS, proto-oncogene c-Fos; Elk1, ETS domain-containing protein Elk-1; Ets1, Protein C-ets-1; SP-1, transcription factor Sp1.

ERK MAPK signalling pathway. The kinase-mediated ERK MAPK signalling is sequentially activated by phosphorylation. ERK1/2 at the terminal kinases in MAPK signalling can translocate to the nucleus to regulate transcription programs, and mediate growth, migration and differentiation. The phosphorylated forms of MEK and ERK are indicated by white circles. Membrane Receptors are presented by grey shapes. Ligands are represented by white triangles. The cytoplasmic receptor is indicated by a thick black arrow. Adapted from (78,79). SOS, son of sevenless; GRB2, growth factor receptor-binding protein 2; p, phosphorylated.

Downstream propagation direction of ERK1/2 kinase signalling in the ERK pathway. ERK1/2 is located in the cytoplasm of normal cells, while activated ERK1/2 is translocated to the nucleus to regulate the activity of transcription factors through phosphorylation. Cytoskeletal components are phosphorylated by ERK1/2 in the cytoplasm. Black arrows indicate signal propagation downstream of ERK. ‘Nuclear activities’ and ‘cytoplasmic activities’ depict ERK activation in the nucleus and cytoplasm, respectively. RSK, ribosomal s6 kinase; MSK, mitogen- and stress-activated protein kinases; MNK, MAP kinase-interacting serine/threonine-protein kinases; cPLA2, cytosolic phospholipase A2; MAP, microtubule-associated protein.

Phosphorylation of upstream protein kinases in the ERK pathway. Curved arrows indicate the downstream targets of ERK. SOS, son of sevenless; GRB2, growth factor receptor-binding protein 2.

Role of ERK/mitogen-activated protein kinase in cancer.

Frequency of mutations in the activator components of the mitogen-activated protein kinase/ERK pathway across different tumours.

Author, year Tumour type KRAS NRAS HRAS BRAF MEK ERK (Refs.)
Colombino et al, 2012; Edlundh-Rose et al, 2006; Namba et al, 2003; Davies et al, 2002; Murugan et al, 2009; Nikolaev et al, 2011; Wang et al, 2007; Jänne et al, 2017 Melanoma 15–29% 20% N/A 90% 3–8% 67–90% (51–58)
Nikolaev et al, 2011; Seo et al, 2012; Cardarella et al, 2013 NSCLC 35% N/A N/A 4% N/A N/A (56,59,60)
Davies et al, 2002; Tol et al, 2009; Jones et al, 2017 Colorectal 40% N/A N/A 5–20% <3% N/A (54,61,62)
Sieben et al, 2004 HGSOC 0–12% N/A N/A N/A N/A N/A (63)
Bell, 2005; Singer et al, 2003 LGSOC 27–36% N/A N/A 33–50% N/A N/A (64,65)
Cardarella et al, 2013; Bansal et al, 2013; Paik et al, 2011 THCA 9–27% 9–27% 9–27% 10–70% N/A N/A (60,66,67)
Bansal et al, 2013; Xing et al, 2013 PTC 20% N/A N/A N/A N/A N/A (66,68)
Singer et al, 2003; Bansal et al, 2013 ATC/FTC N/A 15% N/A N/A N/A N/A (65,66)
Tiacci et al, 2011 Hairy Cell N/A N/A N/A 79–100% N/A N/A (69)
Namba et al, 2003 PDAs 70% N/A N/A N/A N/A N/A (53)
Jones et al, 2017; Xi et al, 2012 AML/ALL 10% N/A N/A N/A N/A N/A (63,70)
Cardarella et al, 2013 BLCA N/A N/A 20% N/A N/A N/A (60)
Paik et al, 2011 RCCs N/A N/A 2% N/A N/A N/A (67)
Davies et al, 2002; Chao et al, 1999; Cheng et al, 2005; Sun et al, 2001 BC <5% N/A N/A 1.2% 7–9% N/A (54,71–73)

NSCLC, non-small cell lung carcinoma; HGSOC, high-grade serous ovarian cancer; LGSOC, low-grade serous ovarian cancer; THCA, thyroid carcinoma; PTC, papillary thyroid cancers; ATC, anaplastic thyroid cancers; FTC, follicular thyroid cancers; PDAs, pancreatic ductal adenocarcinomas; AML, acute myeloid leukaemia; ALL, acute lymphoblastic leukaemia; BLCA, bladder urothelial carcinomas; RCCs, renal cell carcinomas; BC, breast cancer.