The MAPK/ERK signaling pathway: A core hub from basic biology to human diseases

The MAPK/ERK signaling pathway: A core hub from basic biology to human diseases

1. Introduction of the MAPK Pathway

The mitogen-activated protein kinase (MAPK) cascade is a key signaling pathway regulating various cellular processes, including proliferation, differentiation, apoptosis and stress response. The MAPK pathway functions through signal cascades, transmitting extracellular signals to intracellular targets, enabling cells to respond to various specific extracellular stimuli. The MAPK pathway includes three major kinases, namely MAPK kinase-kinase (MAP3K), MAPK kinase (MAPKK), and MAPK, which activate and phosphorylate downstream proteins. Current research has identified four major and distinct MAPK cascade reactions: extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (1, 2, and 3), p38 MAPK (α, β, γ, and δ), and ERK5. This article focuses on the MAPK/ERK signaling pathway.

1.1. The function of MAPK/ERK pathway

The MAPK/ERK pathway is a crucial cellular signaling pathway. Its core function is to amplify and transmit extracellular growth factor signals (such as proliferation-promoting and differentiation-inducing instructions) step by step into the cell nucleus. By activating specific transcription factors, it regulates gene expression and thereby dominates multiple key biological processes of cells, including proliferation, differentiation, survival, and metabolism. Excessive activation of upstream proteins and kinases in the ERK pathway has been proven to induce various diseases, including cancer, inflammation, developmental disorders and neurological diseases. Furthermore, the MAPK/ERK pathway plays a core role in the process of organ regeneration. MAPK/ERK signaling is rapidly activated in response to injury stimuli and coordinates pro-regeneration mechanisms, including cell survival, migration, proliferation, growth, as well as the transcription and translation of related genes.

1.2 Activation Methods of MAPK/ERK pathway

The MAPK/ERK pathway is mainly activated by ligand-stimulated receptor tyrosine kinases (RTK) on the plasma membrane, and can also be activated by G protein-coupled receptors (GPCRS). Then, the RTK signal is transmitted through growth factor receptor-binding protein 2 (Grb2) and SOS, activating the small GTPase Ras, recruiting Ras and Ser/Thr kinase Raf to the plasma membrane to form a complex, and activating Raf by inducing the phosphorylation/dephosphorylation of serine residues on Raf. The active Raf successively phosphorylates and activates MEK1/2. MEK1/2 respectively phosphorylates the ERK1/2 protein, thereby activating ERK1/2. ERK1/2 activates or inactivates multiple proteins through phosphorylation in different subcellular compartments, and can also rapidly shuttle into the cell nucleus to regulate cellular transcriptional activity by phosphorylating multiple transcription factor targets. In addition, ERK1/2 can serve as a negative feedback regulatory mechanism, phosphorylating upstream kinases in the ERK pathway, such as SOS and MEK.

Fig.1 Simplified schematic of the regulatory mechanism and functions of the MAPK/ERK pathway

（The figure is sourced from Int J Mol Sci^[1]）

2. Research related to MAPK/ERK pathway and tumors

Dysfunction of the MAPK/ERK pathway is one of the main causes of the development of various cancers. Multiple studies have found that the activation of the MAPK/ERK signaling pathway can promote the occurrence, proliferation, migration and invasion of cancers such as colorectal cancer (CRC)^[2], breast cancer^[3], ovarian cancer^[4,5], liver cancer^[6], small cell lung cancer^[7], thyroid cancer^[8], and gastric cancer^[9]. Direct or indirect inhibition of MAPK/ERK signaling can suppress tumor proliferation and migration, and weaken malignant phenotypes^[10-12]. MAPK/ERK signal is associated with drug resistance in tumor treatment^[13,14]. Contrary to these results, the MAPK/ERK pathway is a key regulator of the anti-tumor immune sensitivity of glioblastoma (GB) cells^[15]. Experimentally induced ERK phosphorylation in GB cells enhanced the survival rate of immune checkpoint blockade (ICB) therapy, reactivating and generating durable anti-tumor immunity. In addition, a variety of compounds exert pro-apoptotic effects in tumors through the MAPK/ERK pathway^[16-18]. These studies indicate that the activation of the MAPK/ERK pathway is a "double-edged sword" for tumor progression, highlighting its potential value in tumor treatment.

Fig.2 PPP2R1B promotes CRC cells Oxaliplatin sensitivity by MAPK/ERK signaling pathway

（The figure is sourced from Cancer Cell Int^[14]）

3. Research related to MAPK/ERK pathway and autoimmune diseases

The role of MAPK/ERK in autoimmune diseases has been widely studied. The MAPK/ERK pathway mediates the proliferation and migration of fibroblast-like synovial cells (FLs) in rheumatoid arthritis (RA) and may contribute to the progression of RA^[19]. Inhibiting the MAPK/ERK signaling pathway can reduce the proliferation of FLS and alleviate the degree of synovitis in RA^[20]. Spermine alleviates the progression of multiple sclerosis disease model by inhibiting CD4 T cell activation and T effector cell differentiation in a MAPK/ ERK-dependent manner^[21]. Chlorogenic acid can reduce colonic mucosal injury induced by dextran sulfate sodium (DSS), and improve the expression of MAPK/ERK pathway-related proteins in colonic mucosa^[22]. ERK inhibitors reversed the protective effect of chlorogenic acid on colonic tissue. Baicalin n-butyl ester inhibits pyroptosis by binding to ERK protein and suppressing the ROS/ERK/P-ERK/NLRP3 signaling pathway, thereby preventing colitis in mice^[23]. In systemic sclerosis, IL11-dependent ERK signaling mediates the activation of dermal fibroblasts and promotes fibrotic phenotypes^[24]. These results suggest that targeting the MAPK/ERK pathway may be a promising treatment for autoimmune diseases.

4. Research related to MAPK/ERK pathway and cardiovascular diseases

The abnormal activation of the MAPK/ERK signaling pathway is widely involved in the occurrence and development of cardiovascular diseases. Under the stimulation of pressure overload, ERK1/2 phosphorylates and activates ETS2, forming a complex with NFAT, and drives cardiac hypertrophy^[25]. Inhibiting the MAPK/ERK signal transduction can suppress the further hypertrophy of cardiomyocytes^[26]. Down-regulating the MAPK/ERK pathway can prevent ANGII-induced cardiac hypertrophy in mice^[27]. Studies have shown that ERK1/2 signaling is an important regulator of early elastase activation, and its pharmacological inhibition may prevent the progression of aortic valve disease (AVD)^[28]. Andrographolide improves aortic valve proliferation by inhibiting cell proliferation through the MAPK-ERK signaling pathway^[29]. Increased expression of phosphorylated ERK has a protective effect on myocardial ischemia/reperfusion injury, reduces myocardial infarction area, and decreases myocardial cell apoptosis^[30,31]. These results provide assistance for precisely targeting MAPK-ERK for the prevention and treatment of cardiovascular diseases.

5. Research related to MAPK/ERK pathway and Neurodegenerative diseases

The MAPK/ERK pathway is an important pathway related to neuroinflammation during the development of neurodegenerative diseases. Studies have shown that the neuroprotective effect of ginsenoside Rg2 on Alzheimer's disease (AD) may be related to the MAPK-ERK pathway^[32]. Inhibiting the MAPK/ERK pathway can reverse the inhibitory effect of Aβ1-42 peptide on the migration of neural stem cells/progenitor cells (NSPC) and improve the therapeutic effect of NSPC on AD^[33]. Inhibiting MAPK signal transduction in Parkinson's disease (PD) mouse models can rescue neuronal cell death and motor dysfunction^[34]. Inhibiting the MAPK/ERK pathway can reduce abnormal autophagy and apoptosis in cell lines with LRRK2 mutations (one of the causes of PD)^[35]. MAPK/ERK signaling regulates the hypoxia-induced autophagy process, thereby improving the activity of motor neurons with SOD1 mutations (one of the causes of amyotrophic lateral sclerosis)^[36]. Therefore, exploring the specific regulatory mechanism of the MAPK signaling pathway may provide clues for the development of new therapeutic drugs for neurodegenerative diseases.

Fig.3 Proposed mechanism of Tolperisone hydrochloride-induced neuroprotection in PD

（The figure is sourced from Biomed Pharmacother^[34]）

6. Research related to MAPK/ERK pathway and Regeneration

More and more studies have emphasized the significant role of the MAPK/ERK pathway in the process of tissue and organ regeneration. The MAPK/ERK signaling pathway plays a significant role in hematopoietic reconstitution after ionizing radiation^[37]. Low-amplitude electric fields regulate endothelial angiogenesis by activating the MAPK/ERK pathway and promote vascular tissue repair^[38]. It is reported that appropriate activation of MAPK/ERK signaling is beneficial for heart regeneration in zebrafish^[39]. The activation of the MAPK/ERK pathway effectively promotes periodontal bone regeneration and achieves good recovery results^[40]. Notoginsenoside R1 can promote the activation of the MAPK/ERK signaling pathway, down-regulate the expression of TNF-α, and ultimately up-regulate the expression of osteogenic genes, thereby enhancing bone regeneration^[41]. Data indicate that the MAPK/ERK pathway regulates cell proliferation and colony formation in hepatic progenitor cells (HPC) and is a key pathway for liver regeneration^[42]. These evidences highlight the possibility and potential of targeting the MAPK/ERK pathway to induce the regenerative capacity of tissues and organs.

Fig.4 NGR1 can promote bone regeneration

（The figure is sourced from Front Bioeng Biotechnol^[41]）

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