The pathway from HRAS through RAF1 and MEK (MAPKs and ERKs kinases) to ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) regulates many fundamental cellular processes.
Mitogen-activated protein kinase (MAPK) cascades represent one of the major signal systems used by eukaryotic cells to transduce extracellular signals into cellular responses. The stress-activated protein kinases (SAPKs) are MAPKs that are activated by chemical and environmental stresses as well as by proinflammatory cytokines.
The mitogen-activated protein kinase (MAP kinase) pathways include several serine-threonine kinases in three interrelated signal transduction cascades activated by stimuli such as growth factors, stress and inflammation.
Small G proteins such as ras and rac transduce signals from cell surface receptors such as GPCRs and growth factor receptors to multiple tiers of protein kinases that amplify signals and regulate each other.
The endpoints of these cascades include transcription factors that regulate genes involved in inflammation, cell growth and differentiation.
The last tier of kinases, including JNK1, p38, and ERKs, are the MAP Kinases that phosphorylate targets such as c-jun, Elk-1 and other transcription factors.
The JNK pathway is activated by many stimuli including inflammatory factors such as IL-1 and TNF and activates c-jun transcriptional activation. c-Jun, as part of AP-1, activates immediate early genes that are rapidly activated in response to growth factors or inflammatory signals.
The MAP Kinase kinases (MAPKKs), such as the MKK and MEK kinases, are one step up the MAP kinase cascade, phosphorylating and activating Map kinases. Still higher in the cascade are the MAPKKKs (MAP kinase kinase kinase) such as raf.
In mammalian cells, a variety of extracellular stimuli generate intracellular signals that converge on a limited number of so-called mitogen-activated protein kinase (MAPKs)pathways (MAPKs pathways).
The central core of each MAP kinase pathway (MAPKs pathways) is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKKs) phosphorylates and activates a specific MAPK kinase (MAPKKs), which then activates a specific MAPK.
While the ERK-MAPKs are activated by mitogenic stimulation, the CSBP2-MAPKs (MIM.600289) and JNK-MAPKs (MIM.601158) are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors.
A number of scaffolding proteins and endogenous inhibitors have been identified, and their important roles in regulating signalling through this pathway are now emerging. Some scaffolds augment the signal flux, but also mediate crosstalk with other pathways; certain adaptors target MEK-ERK/MAPK complexes to subcellular localizations; others provide regulated inhibition.
Members
| MAPK1 | MAPK2 | MAPK3 | MAPK4 | MAPK5 | MAPK6 | MAPK7 | MAPK8 | MAPK9 |
| MAPK10 | MAPK11 | MAPK12 | MAPK13 | MAPK14 |
See also
References
Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005 Nov;6(11):827-37. PMID: 16227978
Huang C, Jacobson K, Schaller MD. MAP kinases and cell migration. J Cell Sci. 2004 Sep 15;117(Pt 20):4619-28. PMID: 15371522
Olson JM, Hallahan AR. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med. 2004 Mar;10(3):125-9. PMID: 15102355
Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002 Jun;12(6):258-66. PMID: 12074885
Breitkreutz A, Tyers M. MAPK signaling specificity: it takes two to tango. Trends Cell Biol. 2002 Jun;12(6):254-7. PMID: 12074884
Kholodenko BN. MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience? Trends Cell Biol. 2002 Apr;12(4):173-7. PMID: 11978536
Herrera R, Sebolt-Leopold JS. Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends Mol Med. 2002;8(4 Suppl):S27-31. PMID: 11927284
Papatsoris AG, Papavassiliou AG. Molecular ’palpation’ of BPH: a tale of MAPK signalling? Trends Mol Med. 2001 Jul;7(7):288-92. PMID: 11425636
Madhani HD, Fink GR. The riddle of MAP kinase signaling specificity. Trends Genet. 1998 Apr ;14(4):151-5. PMID : 9594663
See also
| CSBPs | ERKs | JNKs |
References
Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci. 2004 Mar;5(3):173-83. PMID: 14976517
Olson JM, Hallahan AR. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med. 2004 Mar;10(3):125-9. PMID: 15102355
Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002 Jun;12(6):258-66. PMID: 12074885
Breitkreutz A, Tyers M. MAPK signaling specificity: it takes two to tango. Trends Cell Biol. 2002 Jun;12(6):254-7. PMID: 12074884
Kholodenko BN. MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience? Trends Cell Biol. 2002 Apr;12(4):173-7. PMID: 11978536
Herrera R, Sebolt-Leopold JS. Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends Mol Med. 2002;8(4 Suppl):S27-31. PMID: 11927284
Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal. 2001 Nov;13(11):777-85. PMID: 11583913
Papatsoris AG, Papavassiliou AG. Molecular ’palpation’ of BPH: a tale of MAPK signalling? Trends Mol Med. 2001 Jul;7(7):288-92. PMID: 11425636
Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001 Mar 1;410(6824):37-40. PMID: 11242034
Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J. 2000 Nov;14(14):2147-57. PMID: 11053235
Fanger GR. Regulation of the MAPK family members: role of subcellular localization and architectural organization. Histol Histopathol. 1999 Jul;14(3):887-94. PMID: 10425559
Garrington TP, Johnson GL. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol. 1999 Apr;11(2):211-8. PMID: 10209154
Madhani HD, Fink GR. The riddle of MAP kinase signaling specificity. Trends Genet. 1998 Apr ;14(4):151-5. PMID : 9594663