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MAPK signaling - @ a glance

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    Mitogen-activated protein kinases (MAPK) are a family serine/threonine kinases which function in tiered protein kinase cascades. They regulate proliferation, apoptosis, differentiation and survival - over and under-activation of this family of proteins have been linked to malignancy1, neurodegeneration2 and cardiovascular disease3. Each MAPK can be activated by associated MAPK kinases (MAPKK) through dual phosphorylation which is subsequently activated by MAPKK kinases (MAPKKK)4.

 

Download the MAPK signaling pathway card

 

Through this mechanism MAPK signaling can amplify initial stimuli and regulate a diverse range of responses. Specificity and complexity of the MAPK signaling pathway is regulated by a number of mechanisms:

Activation and substrate specificity

Every level of the MAPK signaling cascade is subject to target specificity. This allows amplification of precise downstream signaling and transcription factors.

  • MAPKKK - Different intracellular (DNA damage, oxident stress etc.) and extracellular (cytokines, GF, stress etc.) signals activate specific MAPKKKs. Once activated, many MAPKKKs have broad specificity towards target MAPKK proteins, particularly between JNK and p38 signaling.
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  • MAPKK - MAPKKs show increased specificity towards targets dependent on cell type and stimuli5.
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  • MAPK - Once phosphorylated each MAPK can activate a wide range of nuclear and cytoplasmic targets - over 100 have been identified for ERK signaling alone6.
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Tissue specific expression - All levels of MAPK signaling is subject to specific tissue distribution. These tissue distributions are a major form of signaling regulation ensuring the correct pathways are activated in specific areas7.

Subcellular localization - Scaffold proteins regulate protein availability and subcellular localization which are important regulators of signal transduction and will heavily influence the final cellular outcome of MAPK activation.

Alternative activation - Activation of MAPK pathways does not always follow the traditional pattern. In some cases MAPK can be activated directly without MAPKKs and MAPKKKs8

 

MAPK products

 

ProductBiological descriptionPurityReference
JNK      
SP600125 JNK inhibitor 98% Heo et al, 2004
TCS JNK 5a Selective JNK2/3 inhibitor 99% Angell et al, 2007
MKK/MEK      
Myricetin Potent anti-neoplastic, anti-oxidant and anti-inflammatory 97% Hagenacker et al, 2010
PD 0325901 Potent MEK 1 and 2 inhibitor 99% Sheth et al, 2011
U0126 Selective MKK inhibitor 98% Favata et al, 1998
MNK      
CGP 57380 MNK inhibitor 98% Knauf et al, 2010
p38      
SB 202190 Highly selective, potent, cell permeable p38 MAP kinase inhibitor 99% Menon et al, 2011
SB 203580 p38 MAP kinase inhibitor 99% Cuenda et al, 2007
SB 203580 hydrochloride p38 MAP kinase inhibitor; water soluble 99% Kumar et al, 1999
Raf      
ZM 336372 Potent, selective c-Raf inhibitor 98% Hall-Jackson et al, 1999
General      
Anisomycin Protein synthesis inhibitor 98% Xiong et al, 2006
(-)-Epigallocatechin Gallate Potent anti-oxidant flavonoid 98% Khan et al, 2006
Hydralazine hydrochloride DNA methylation inhibitor. Anti-hypertensive agent 99% Sato et al, 2003
Isoprenaline hydrochloride Non selective β-adrenoceptor agonist 99% Brouri et al, 2004
2-Methoxyestradiol Potent antitumor and antiangiogenic agent 98% Shimada et al, 2003

 

Useful resources from our technical team

  • Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002
  • Haeusgen W et al. The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. Eur J Cell Biol 90(6-7):536-44 (2011). Read more (PubMed: 21333379) »
  • Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J 429(3):403-17 (2010). Read more (PubMed: 20626350) »
  • Santarpia L et al. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets.16(1):103-19 (2012). Read more (PubMed: 22239440) »
  • Drew BA et al. MEK5/ERK5 pathway: the first fifteen years. Biochim Biophys Acta. 2012 1825(1):37-48 (2012). Read more (PubMed: 22020294) »

References

  1. Raman M et al. Differential regulation and properties of MAPKs. Oncogene 26(22):3100-12 (2007). Read more (PubMed: 17496909) »
  2. Dhillon AS et al. MAP kinase signalling pathways in cancer.Oncogene. 26(22):3279-90 (2007). Read more (PubMed: 17496922) »
  3. Munoz L and Ammit AJ.Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology 58(3):561-8 (2010). Read more (PubMed: 19951717) »
  4. Muslin AJ. MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond) 115(7):203-18 (2008). Read more (PubMed: 18752467) »
  5. Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J 429(3):403-17 (2010). Read more (PubMed: 20626350) »
  6. Enslen H et al. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem 273(3):1741-8 (1998). Read more (PubMed: 9430721) »
  7. Ramos JW. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int J Biochem Cell Biol 40(12):2707-19 (2008). Read more (PubMed: 18562239) »
  8. Ge B et al. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science 295(5558):1291-4 (2002). Read more (PubMed: 11847341) »

 

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