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The mitogen-activated protein kinase (MAPK) pathway.[1][2][3][4][5][6][7][8][9][10]

Mitogen-activated protein (MAP) kinases (EC are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.[11]

Overview of signal transduction pathways involved in apoptosis.



MAPKs are involved in the action of most nonnuclear oncogenes. They are involved in cell response to growth factors such as BDNF or nerve growth factor. Extracellular stimuli lead to activation of a MAP kinase via a signaling cascade ("MAPK cascade") composed of MAP kinase, MAP kinase kinase (MKK, MEKK, or MAP2K), and MAP kinase kinase kinase (MKKK or MAP3K, EC

MAP kinase activation
MAP kinase kinase kinase


MAP kinase kinase

(MAP2K or MKK)

MAP kinase
further signalling

A MAP3K that is activated by extracellular stimuli phosphorylates a MAP2K on its serine and threonine residues, and then this MAP2K activates a MAP kinase through phosphorylation on its serine and tyrosine residues. (ie MAP2K can be a dual-specificity kinase). This MAP kinase signaling cascade has been evolutionarily well-conserved from yeast to mammals.


To date, six distinct groups of MAPKs have been characterized in mammals:

  1. extracellular signal-regulated kinases (ERK1, ERK2). The ERK1/2 (also known as classical MAP kinases) signaling pathway is preferentially activated in response to growth factors and phorbol ester (a tumor promoter), and regulates cell proliferation and cell differentiation.
  2. c-Jun N-terminal kinases (JNKs), (MAPK8,MAPK9,MAPK10) also known as stress-activated protein kinases (SAPKs).
  3. p38 isoforms.(p38-α(MAPK14), -β(MAPK11), -γ (MAPK12 or ERK6) and -δ(MAPK13 or SAPK4)) Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis.
  4. ERK5. ERK5 (MAPK7), which has been found recently, is activated both by growth factors and by stress stimuli, and it participates in cell proliferation.
  5. ERK3/4. ERK3 (MAPK6) and ERK4 (MAPK4) are structurally related atypical MAPKs possessing SEG motifs in the activation loop and displaying major differences only in the C-terminal extension. ERK3 and ERK4 are primarily cytoplasmic proteins which bind, translocate and activate MK5 (PRAK, MAPKAP5). ERK3 is unstable, unlike ERK4 which is relatively stable.[12]
  6. ERK7/8. (MAPK15) This is the newest member of MAPKs and behaves like atypical MAPKs. It possesses a long C terminus similar to ERK3/4.

See also


  1. ^ Rossomando AJ, Payne DM, Weber MJ, Sturgill TW (1989). "Evidence that pp42, a major tyrosine kinase target protein, is a mitogen-activated serine/threonine protein kinase". Proc Natl Acad Sci USA 86 (18): 6940–3. doi:10.1073/pnas.86.18.6940. PMID 2550926.  
  2. ^ Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999). "Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms". Science 286 (5443): 1358–62. doi:10.1126/science.286.5443.1358. PMID 10558990.  
  3. ^ Chadee DN, Yuasa T, Kyriakis JM (2002). "Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2". Mol. Cell. Biol. 22 (3): 737–49. doi:10.1128/MCB.22.3.737-749.2002 (inactive 2008-06-22). PMID 11784851.  
  4. ^ Chang L, Karin M (2001). "Mammalian MAP kinase signaling cascades". Nature 410 (6824): 37–40. doi:10.1038/35065000. PMID 11242034.  
  5. ^ Chen YR, Tan TH (2000). "The c-Jun N-terminal kinase pathway and apoptotic signaling (review)". Int. J. Oncol. 16 (4): 651–62. PMID 10717232.  
  6. ^ Hazzalin CA, Mahadevan LC (2002). "MAPK-regulated transcription: a continuously variable gene switch?". Nat. Rev. Mol. Cell Biol. 3 (1): 30–40. doi:10.1038/nrm715. PMID 11823796.  
  7. ^ Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD (1997). "BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C". EMBO J. 16 (23): 7054–66. doi:10.1093/emboj/16.23.7054. PMID 9384584.  
  8. ^ Kiefer F, Tibbles LA, Anafi M, Janssen A, Zanke BW, Lassam N, Pawson T, Woodgett JR, Iscove NN (1996). "HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway". EMBO J. 15 (24): 7013–25. PMID 9003777.  
  9. ^ Pearson G, English JM, White MA, Cobb MH (2001). "ERK5 and ERK2 cooperate to regulate NF-kappaB and cell transformation". J. Biol. Chem. 276 (11): 7927–31. doi:10.1074/jbc.M009764200. PMID 11118448.  
  10. ^ Weston CR, Lambright DG, Davis RJ (2002). "Signal transduction. MAP kinase signaling specificity". Science 296 (5577): 2345–7. doi:10.1126/science.1073344. PMID 12089430.  
  11. ^ Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001). "Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions". Endocr. Rev. 22 (2): 153–83. doi:10.1210/er.22.2.153. PMID 11294822.  
  12. ^ Kant S, Schumacher S, Singh MK, Kispert A, Kotlyarov A, Gaestel M. (2006). "Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5". J Biol Chem. 281 (46): 35511–9. doi:10.1074/jbc.M606693200. PMID 16973613.  

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