MAPK Cell Signaling Pathway

Classical mitogen-activated protein kinase (MAPK) pathway activation begins at the cell membrane, where small GTPases and various protein kinases phosphorylate and activate MAPKKKs. Subsequently, MAPKKKs directly phosphorylate MAPKKs, which, once activated, phosphorylate MAPKs. Activated MAPKs interact with and phosphorylate numerous cytoplasmic substrates and ultimately modulate transcription factors that drive context-specific gene expression. This, in turn, results in various biological responses, for example osmotic shock, cell cycle progression, or induction of interferon production ^[8].

There are at least three distinct MAPK signaling modules which mediate extracellular signals into the nucleus to turn on the responsive genes in mammalian cells. These include ERK, JNK, and p38 kinase.

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. Thermo Scientific™ has a wide range of products to help with MAPK research.

MAPK also interacts with other pathway targets:

The ERK kinase family consists of ERK 1 and 2. They are activated in response to several growth factors and mitogens. The activation of ERK begins with the phosphorylation of MEK, followed by the phosphorylation of the theronine and tyrosine residues. After ERK has been activated it moves to the cytoplasm and nucleus to phosphorylate other proteins. These proteins are responsible for cell regulation, growth, differentiation, and mitosis ^{[1, 2, 5]}.

The JNK kinase family consists of JNK1, JNK2, and JNK3. JNK1 and 2 are present in all tissues; however, JNK3 is only located in the brain, heart and testes. JNK is activated in response to cytokines, growth factors, pathogens, stess, etc. JNK is linked to the transformation of oncogene and growth factor pathways. Irregularities in JNK activity have been linked to cancer, diabetes, inflammatory disorders and neurodegenerative disorders. ERK to JNK cross-activation has been seen. JNK is the final facilitator for ERK to stimulate cell proliferation ^{[2, 3, 5]}.

The kinase p38, is activated in response to a variety of extracellular stimuli including osmotic shock, inflammatory cytokines, lipopolysaccharides (LPS), anisomycin, UV light and growth factors. The activation of p38 is mediated by several upstream kinases including MAP kinase kinase 3 (MKK3), MAP kinase kinase 6 (MKK6) and MAP kinase kinase 4 (MKK4, also known as SEK1 and JNKK1). These kinases phosphorylate p38 at threonine 180 and tyrosine 182, resulting in p38 activation. p38 is linked to asthma, autoimmunity, and inflammation ^[4].

Although MAPK signaling cascades are depicted as simple linear, unidirectional groups of protein kinases, the pathway is highly complex. 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 and JAK-STAT pathways are well documented ^[7].

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2. Zhang, W. et al (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Research. 12: 9-18.
3. Bubici, C. et al. (2014) JNK signaling in cancer: in need of new, smarter therapeutic targets. British Journal of Pharmacology. 171: 24-37.
4. Johnson, G. et al. (2002) Mitogen-activated protein kinase pathways mediate by ERK, JNK, and p38 protein kinases. Science. 298.
5. Fey, D. et al (2012) Crosstalk and signaling switched in mitogen-activated protein kinases cascades. Frontiers in Physiology 3: 1-21.
6. Roberts, P.J. et al (2007) Targeting the Raf-MEK-ERK-mitogen activated protein kinase cascade for treatment of cancer. Oncogene 26(22): 3291-3310.
7. Carracedo P. et al (2008) The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 27(41): 5527-5541.
8. Cargnello M. et al (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75(1): 50-83.