The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. The pathway covers many proteins, including MAPK originally named ERK (extracellular signal-regulated kinases), which transmits signal by phosphorylates a neighboring protein, as like an "on" or "off" switch.
The MAPK signaling pathway is essential in regulating many cellular processes including inflammation, cell stress response, cell differentiation, cell division, cell proliferation, metabolism, motility and apoptosis. The role of the MAPK pathway in cancer, immune disorders and neurodegenerative diseases has been well recognized.
Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5 that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5.
But each MAPKK can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signaling. Presumably each MAPKKK confers responsiveness to distinct stimuli. As shown in the following picture, Classical mitogen-activated protein kinase (MAPK) pathway activation begins at the cell membrane where small GTPases and various protein kinases phosphorylate MAPKKKs. Subsequently, MAPKKKs directly phosphorylate and activate MAPKKs. Once phosphorylated, activated MAPKs phosphorylate numerous cytoplasmic substrates and ultimately modulate transcription factors that drive context-specific gene expression.
Although MAPK signaling cascades are depicted as simple linear, unidirectional groups of protein kinases, the pathway is highly complex, actually. A large degree of cross-talk within the MAPK cascades and other signaling networks exists. For example, interactions between mediators of the MAPK, PI3K networks, NFκB pathway and JAK-STAT pathway are well documented.
The MAPK signaling pathway is closely related to cell proliferation and differentiation. Continuous activation of MAPK signals is found in many malignant tumors. Cell proliferation contributes largely to tumorigenesis. And tumorous metastasis and invasion are lethal causes. Among the mammalian MAPK pathways, the ERK pathway is the best-studied and is deregulated in about one-third of human cancers. The ERK1/2 pathway plays an important role in proliferation, differentiation, metastasis, and invasion of tumor cells. Wen-Horng Wang, et al. found that the hepatitis b virus x protein inactivated p53 gene through the p38/MAPK pathway, thus inducing the primary liver cancer (PLC). Kim MS, et al. demonstrated that p38 MAPK is a key signal molecule in breast cancer cells' invasion and metastasis induced by Ras. And many studies showed that the p38 MAPK pathway exerts important regulatory functions in MMPs (matrix metalloproteinases) produced by extracellular stimuli. MMPs are a type of proteolytic enzyme tightly associated with tumorous invasion and migration. Besides, the p38 MAPK pathway promotes tumor angiogenesis necessary to maintain tumor cell growth.
Cancer is often exposed to a variety of stress conditions such as oxygen deprivation and inflammation. Many MAPK pathways are involved in stress signaling. Therefore, some kinases are activated by stress in cancer in response to inflammation, DNA damage, and apoptosis. Hypoxic states are widespread in solid tumors. The hypoxic signal stimulates the activation of MKP-1. MKP-1 further activates SAPK/JNKs, which activates c-Jun. Active c-Jun promotes multiple downstream genes transcription that is important for cancer cells' proliferation and survival.
Aberrations in MAPK signaling influences most processes of carcinogenesis, and are crucial for the development and progression of cancer. Most cancer-associated lesions such as overexpression of receptor tyrosine kinases, activating mutations in receptor tyrosine kinases, sustained autocrine or paracrine production of activating ligands, Ras mutations and B-Raf mutations result in constitutive activation of ERK signaling. JNK activity and phosphorylation of c-Jun has been reported to play a critical role in Ras-induced tumorigenesis.
|KRAS||KRAS Antibody||KRAS Protein||KRAS cDNA||KRAS ELISA Kit|
|LAMTOR3||LAMTOR3 Antibody||LAMTOR3 Protein||LAMTOR3 cDNA||LAMTOR3 ELISA Kit|
|MAP2K1||MAP2K1 Antibody||MAP2K1 Protein||MAP2K1 cDNA||MAP2K1 ELISA Kit|
|MAP2K2||MAP2K2 Antibody||MAP2K2 Protein||MAP2K2 cDNA||MAP2K2 ELISA Kit|
|MAP2K3||MAP2K3 Antibody||MAP2K3 Protein||MAP2K3 cDNA||MAP2K3 ELISA Kit|
|MAP2K4||MAP2K4 Antibody||MAP2K4 Protein||MAP2K4 cDNA||MAP2K4 ELISA Kit|
|MAP2K5||MAP2K5 Antibody||MAP2K5 Protein||MAP2K5 cDNA||MAP2K5 ELISA Kit|
|MAP2K6||MAP2K6 Antibody||MAP2K6 Protein||MAP2K6 cDNA||MAP2K6 ELISA Kit|
|MAP2K7||MAP2K7 Antibody||MAP2K7 Protein||MAP2K7 cDNA||MAP2K7 ELISA Kit|
|MAP3K1||MAP3K1 Antibody||MAP3K1 Protein||MAP3K1 cDNA||MAP3K1 ELISA Kit|
|MAP3K11||MAP3K11 Antibody||MAP3K11 Protein||MAP3K11 cDNA||MAP3K11 ELISA Kit|
|MAP3K12||MAP3K12 Antibody||MAP3K12 Protein||MAP3K12 cDNA||MAP3K12 ELISA Kit|
|MAP3K13||MAP3K13 Antibody||MAP3K13 Protein||MAP3K13 cDNA||MAP3K13 ELISA Kit|
|MAP3K14||MAP3K14 Antibody||MAP3K14 Protein||MAP3K14 cDNA||MAP3K14 ELISA Kit|
|MAP3K2||MAP3K2 Antibody||MAP3K2 Protein||MAP3K2 cDNA||MAP3K2 ELISA Kit|
|MAP3K20||MAP3K20 Antibody||MAP3K20 Protein||MAP3K20 cDNA||MAP3K20 ELISA Kit|
|MAP3K3||MAP3K3 Antibody||MAP3K3 Protein||MAP3K3 cDNA||MAP3K3 ELISA Kit|
|MAP3K4||MAP3K4 Antibody||MAP3K4 Protein||MAP3K4 cDNA||MAP3K4 ELISA Kit|
|MAP3K5||MAP3K5 Antibody||MAP3K5 Protein||MAP3K5 cDNA||MAP3K5 ELISA Kit|
|MAP3K6||MAP3K6 Antibody||MAP3K6 Protein||MAP3K6 cDNA||MAP3K6 ELISA Kit|