Mitogen-activated protein kinases (MAPKs) are a class of serine/threonine protein kinases widely present in eukaryotic cells. MAPK signaling pathway is one of the important signaling systems in cells and plays an important role in various physiological and pathological processes such as cell growth, proliferation, differentiation, transformation, apoptosis, and angiogenesis. In recent years, it has been found that there are four main pathways in the MAPK family: extracellular signal regulated kinases (ERK1/2); c-Jun N-terminal kinase (c-Jun N-terminal kinase, JNK); P38 mitogen-activated protein kinase; ERK5. The ERK1/2, JNK, P38, and ERK5 pathways mediate different biological effects. At the same time, there is a wide interaction between these pathways, which can play a synergistic or mutually inhibiting role. Among them, ERK is the earliest discovered MAPK member, which is most widely studied and plays an important role in the occurrence and development of tumors. The ERK-associated intracellular signaling pathway is thought to be the classical MAPK pathway, an important part of a series of kinase enzymatic cascades that transduce extracellular stimuli from the cell membrane into the nucleus.
MAPK signaling pathway
The MAPK signal pathway consists of three core kinases (MAP3K, MAPKK, and MAPK), with upstream (MAP4K) and downstream components (MAPKAPK). MAPK signaling pathway activation is performed by performing a conserved three-stage enzymatic cascade: phosphorylation of MAP3K activates MAPKK (phosphorylation) and ultimately activates MAPK (phosphorylation). The MAPK signaling pathway mainly includes the ERK1 /2 pathway, the JNK pathway, the P38 pathway, and the ERK5 pathway.
Figure 1. MAPK signaling pathways
The ERK1/2 pathway is activated by stimulation of growth factors, hormones, G protein-linked receptor ligands, cytokines, TGF, and osmotic pressure. The classic activation path of ERK1/2 signal path is: Ras→ Raf→ MEK1 /2→ ERK1 /2. Activated ERK1/2 enters the nucleus via nuclear translocation and then activates its downstream related transcription factors Ets-1, ATF-2, c-Fos, c-Myc, Elk-1 or NF-κB, or activates cytoplasmic and cellular nuclear kinase MNKs, MPKAP-2, RSK, MSKs, etc., then regulates cell survival, proliferation and differentiation.
Figure 2. Activation of the Ras/Raf/MEK/ERK signaling pathway
The c-Jun N-terminal kinase (JNK) is located in the cytoplasm, also known as stress activated protein kinase (SAPK). A variety of signal stimuli can mediate JNK activation, such as growth factors, cytokines, and environmental stress. Activated JNK regulates various life processes such as embryonic development, cell growth, oncogene transformation, cell differentiation, and apoptosis. The JNK genes include JNK1 (SAPKα), JNK2 (SAPKβ), and JNK3 (SAPKγ). JNK1 and JNK2 are expressed in almost all cells, and JNK3 is expressed mainly in the brain, heart, and testis. The activation path of JNK pathway is: MEKK1-4, MLK1-3 and DLK→MKK4, MKK7→JNKs. JNK can activate different transcription factors (AP-1, c-Jun, ATF-2, Elk-1, c-Myc, p53, Bad, MLK2) and some Bcl-2 family members. Recent studies have further found that the JNK signaling pathway is closely related to apoptosis in idiopathic pulmonary fibrosis apoptosis.
P38 can be activated by inflammatory mediators (TNFα, IL-6 or IL-1) or anti-inflammatory factors (EGF, TGF-β), ultraviolet radiation, heat or osmotic shock. It has been found that p38MAPK has four isoforms, namely p38α ( MAPK14 ), p38β ( MAPK11 ), p38γ ( MAPK12 ) and p38δ ( MAPK13 ). P38α and p38β are widely present in various tissue cells, and p38γ and p38δ are expressed only in muscle, testis, pancreas, lung, kidney or endocrine glands. The activation pathway of the P38 pathway is: Mlk1-3, MEKK1-4, TAK, ASK1/2→MEK3, and MEK6→P38. Activation of P38 activates the transcription factors ATF-2, NF-ΚB, Elk-1, Max, MEF-2, Max, p53, Stat1 and so on. JNK and p38 MAPK are usually activated by some inflammatory cytokines or external stress, mainly regulating the expression of cytokines and apoptosis. The p38MAPK signaling pathway is an important member of the MAPK family, and its resting state is mainly distributed in the cytoplasm. Phosphorylation can be induced by hypoxia, ultraviolet light, and other factors, and transferred to the nucleus. It plays a key role in regulating inflammatory response and wound healing by regulating the activity of transcription factors and the synthesis of cytokines.
Figure 3. p38 MAP kinase signaling pathways in response to several stimuli
Many studies have demonstrated that cytokines are involved in tissue ischemia/reperfusion injury through a variety of pathways. Cytokine production is closely related to the p38 MAPK pathway. The oxides produced by reperfusion can activate p38 MAPK, which in turn leads to increased cytokine production and tissue ischemia/reperfusion injury. Inhibition of p38 MAPK protects tissue ischemia/reperfusion injury.
ERK5 (extracellular signal-regulated kinase 5), also known as large MAPK-1 (BMK - 1), can be activated by hyperosmotic pressure, hypoxia, oxidant, fluid shear, and growth factors. The activation pathway of ERK5 is: MEKK2 / MEKK3→MEK5→ERK5. Studies have shown that ERK5 phosphorylation increases and cells proliferate in osteoblasts after cyclic fluid shear. The ERK5 signaling pathway plays an important role in angiogenesis, cardiac development, and neural cell differentiation.
MAPK and tumor
Tumor tissue needs a constant blood supply to maintain its growth and metastasis. It will complete the vascular renewal in various ways to meet its nutritional needs. The MAPK/ERK signaling pathway is the regulatory center of various angiogenic signaling pathways that determine the final growth state of the blood vessels. A variety of angiogenic factors can activate the MAPK/ERK pathway and up-regulate vascular endothelial growth factor levels. The vascular endothelial cell angiogenesis was studied by Matrigel gel mimicking the physiological state of the body. It was found that PD98059, a MAPK/ERK signaling pathway inhibitor, significantly inhibited the formation of vascular endothelial cells. And as the concentration of the inhibitor increases, the length of the pipe formation gradually decreases. This indicates that the MAPK/ERK signal channel is involved in the formation of the vascular canal.
The use of MEK/ERK signaling pathway inhibitors revealed that horizontal, vertical and directed migration of tumor vascular endothelial cells was inhibited and positively correlated with inhibitor concentration, indicating that ERK signaling pathway is involved in tumor blood vessel growth and migration. In addition, phosphorylation of ERK is involved in signal transduction of angiogenesis-related factors, activates transcription factors, and promotes angiogenesis. In most cancer tissues, the correlation between ERK and VEGF found that ERK1 and VEGF were positively correlated, suggesting that they synergistically promote tumor invasion and metastasis in the occurrence and development of cancer.
MAPK and rheumatoid arthritis
In rheumatoid arthritis (RA), p38 mitogen-activated protein (MAP) kinase plays a key role because it regulates the production of pathogenic cytokines such as interleukin (IL-1) and tumor necrosis factor (TNF-α) through a variety of transcriptional and translational mechanisms. In the synovial tissue of RA, p38 is highly expressed and activated, and the commonly used p38 MAPK inhibitor SB203580 reduces the production of pro-inflammatory cytokines by monocytes/macrophages, neutrophils and T lymphocytes. In a rodent model of RA, p38 MAPK inhibitors can inhibit inflammation and bone destruction.
In addition, p38 is also involved in other inflammation-related events such as neutrophil activation, apoptosis, and induction of nitric oxide synthase. The p38 protein kinase has two major upstream activators: MKK3 and MKK6. Studies in mice that are knocked out the MKK3 and MKK6 genes have shown that both are required for full p38 MAPK activation in vivo. Phosphorylation of MKK3 /6 is highly expressed in the RA synovium, especially in the intimal lining. Increased phosphorylation of MKK3 and -MKK6 exacerbates bone destruction and inflammation of the synovium in animal models of arthritis. MKK3 and MKK6 may be potential pathways for activation of the rheumatoid synovial membrane p38 MAPK to enhance cytokine and protease production.
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