MAPK Signaling Pathway (Homo sapiens)

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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. 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. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli. Source: KEGG


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  1. Chen CY, Weng YH, Chien KY, Lin KJ, Yeh TH, Cheng YP, Lu CS, Wang HL; ''(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD.''; Cell Death Differ, 2012 PubMed Europe PMC Scholia
  2. Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH; ''MAP kinases.''; Chem Rev, 2001 PubMed Europe PMC Scholia
  3. Zhu X, Lee HG, Raina AK, Perry G, Smith MA; ''The role of mitogen-activated protein kinase pathways in Alzheimer's disease.''; Neurosignals, 2002 PubMed Europe PMC Scholia
  4. Takeda K, Ichijo H; ''Neuronal p38 MAPK signalling: an emerging regulator of cell fate and function in the nervous system.''; Genes Cells, 2002 PubMed Europe PMC Scholia
  5. Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S; ''MAPK pathways in radiation responses.''; Oncogene, 2003 PubMed Europe PMC Scholia
  6. Abell AN, Granger DA, Johnson GL; ''MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta.''; J Biol Chem, 2007 PubMed Europe PMC Scholia
  7. Tanoue T, Nishida E; ''Docking interactions in the mitogen-activated protein kinase cascades.''; Pharmacol Ther, 2002 PubMed Europe PMC Scholia
  8. Harper SJ, LoGrasso P; ''Signalling for survival and death in neurones: the role of stress-activated kinases, JNK and p38.''; Cell Signal, 2001 PubMed Europe PMC Scholia
  9. Huang EJ, Reichardt LF; ''Trk receptors: roles in neuronal signal transduction.''; Annu Rev Biochem, 2003 PubMed Europe PMC Scholia
  10. Cho H, Lee J, Kwak NJ, Lee KH, Rha S, Kim YH, Cho YY, Yang KH, Kim K, Lim Y; ''Silica induces nuclear factor-kappaB activation through TAK1 and NIK in Rat2 cell line.''; Toxicol Lett, 2003 PubMed Europe PMC Scholia
  11. Yang SH, Sharrocks AD, Whitmarsh AJ; ''Transcriptional regulation by the MAP kinase signaling cascades.''; Gene, 2003 PubMed Europe PMC Scholia


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113991view09:34, 15 December 2020EgonwThree more pathways clickable
112161view18:28, 29 September 2020Khanspersfixed ptm state comments
110569view22:37, 18 May 2020Khanspersadded phosphosite for RAF1
107148view14:23, 17 September 2019MaintBotChEBI identifier normalization
106635view20:59, 12 September 2019KhanspersModified description
106182view12:07, 16 August 2019MaintBotHMDB identifier normalization
105440view04:52, 8 August 2019KhanspersModified description
105253view22:42, 24 July 2019Khanspersupdated phosphosites
105246view00:02, 24 July 2019Khanspersminor update
105245view23:50, 23 July 2019Khanspersupdating phosphosites
105244view23:47, 23 July 2019Khanspersupdating phosphosites
105243view23:41, 23 July 2019Khanspersupdating phospho sites
103466view19:21, 5 March 2019AlexanderPicoModified description
103464view19:19, 5 March 2019AlexanderPicoModified description
96995view21:30, 25 April 2018Khanspersadded phosphosites
96304view18:29, 7 March 2018EgonwReplaced secondary ChEBI identifiers with primary identifiers.
95114view14:52, 16 November 2017DeSlFIxed nested group.
94850view22:30, 9 October 2017Khanspersadded phosphorylation information as comments on states
94694view23:16, 4 October 2017Khanspersremoved old GenMAPP comments
94606view20:31, 29 September 2017Khanspersconnected lines and updated layout
94603view21:25, 28 September 2017Khanspersdefined FGF and calcium channels
94570view13:56, 28 September 2017DeSlChanged IDs of HMDB (removed 2 zero's, to use the primary ID).
94567view23:33, 27 September 2017Khanspersoverhaul in progress
94566view23:08, 27 September 2017Khanspersoverhaul in progress
94565view19:23, 27 September 2017Khanspersoverhaul - in progress
79951view11:12, 28 April 2015ZariChanged Entrez gene Id to Ensembl Id for MAP3K14
72103view21:47, 24 October 2013Mkutmonadded datasource for "Wnt signaling pathway", "Apoptosis" and "Cell cycle"
70631view00:25, 20 August 2013MaintBotUpdated xrefs by Anatoly Urisman
70021view01:51, 12 July 2013AlexanderPicoModified title
68899view17:29, 8 July 2013MaintBotUpdated to 2013 gpml schema
67443view11:02, 26 June 2013DdiglesOntology Term : 'mitogen activated protein kinase signaling pathway' added !
54211view22:33, 23 November 2012AlexanderPicoAdded Vemurafenib
54210view22:29, 23 November 2012AlexanderPicoAdded lrrk2
44890view10:14, 6 October 2011MartijnVanIerselOntology Term : 'MAPK signaling pathway' added !
41048view23:16, 1 March 2011MaintBotRemoved redundant pathway information and comments
38878view18:52, 24 September 2010KhanspersAdded pathway links and changed line types
38877view18:44, 24 September 2010Khanspers
37347view17:34, 28 May 2010KhanspersConnectors
35657view22:02, 12 February 2010KhanspersLit Refs
35656view22:01, 12 February 2010KhanspersLiterature references
35655view21:59, 12 February 2010KhanspersLiterature references
35654view21:49, 12 February 2010KhanspersModified description
32414view17:06, 15 August 2009MaintBotFixed text labels
32071view13:36, 14 August 2009MaintBotFixed group labels
28779view12:49, 6 March 2009BingoGADD45A-MAP3K4 literature link
21482view11:31, 14 November 2008MaintBot[[Pathway:Homo sapiens:MAPK signaling pathway KEGG]] moved to [[Pathway:WP382]]: Moved to stable identifier
15384view21:59, 27 May 2008KhanspersAdded link to pathway
15380view21:35, 27 May 2008Khanspersadded connectors and changed labels
15378view21:34, 27 May 2008KhanspersPeriodical save, work in progress
15375view21:14, 27 May 2008KhanspersPeriodical save, work in progress

External references


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NameTypeDatabase referenceComment
ACVR1BGeneProduct91 (Entrez Gene)
ACVR1CGeneProduct130399 (Entrez Gene)
AKT1GeneProduct207 (Entrez Gene)
AKT2GeneProduct208 (Entrez Gene)
AKT3GeneProduct10000 (Entrez Gene)
ARRB1GeneProduct408 (Entrez Gene)
ARRB2GeneProduct409 (Entrez Gene)
ATF2GeneProduct1386 (Entrez Gene)
ATF4GeneProduct468 (Entrez Gene)
BDNFGeneProduct627 (Entrez Gene)
BRAF V600EGeneProduct673 (Entrez Gene)
BRAFGeneProduct673 (Entrez Gene)
CASP1GeneProduct834 (Entrez Gene)
CASP2GeneProduct835 (Entrez Gene)
CASP3GeneProduct836 (Entrez Gene)
CASP6GeneProduct839 (Entrez Gene)
CASP7GeneProduct840 (Entrez Gene)
CASP8GeneProduct841 (Entrez Gene)
CASP9GeneProduct842 (Entrez Gene)
CD14GeneProduct929 (Entrez Gene)
CDC25BGeneProduct994 (Entrez Gene)
CDC42GeneProduct998 (Entrez Gene)
CRKGeneProduct1398 (Entrez Gene)
CRKLGeneProduct1399 (Entrez Gene)
Cell cyclePathwayWP179
DAXXGeneProduct1616 (Entrez Gene)
DDIT3GeneProduct1649 (Entrez Gene)
DUSP10GeneProduct11221 (Entrez Gene)
DUSP1GeneProduct1843 (Entrez Gene)
DUSP4GeneProduct1846 (Entrez Gene)
DUSP5GeneProduct1847 (Entrez Gene)
DUSP6GeneProduct1848 (Entrez Gene)
DUSP7GeneProduct1849 (Entrez Gene)
EGFGeneProduct1950 (Entrez Gene)
EGFRGeneProduct1956 (Entrez Gene)
ELK1GeneProduct2002 (Entrez Gene)
FASGeneProduct355 (Entrez Gene)
FASLGGeneProduct356 (Entrez Gene)
FGF4GeneProduct2249 (Entrez Gene)
FLNAGeneProduct2316 (Entrez Gene)
FOSGeneProduct2353 (Entrez Gene)
GADD45AGeneProduct1647 (Entrez Gene)
GCKGeneProduct2645 (Entrez Gene)
GNA12GeneProduct2768 (Entrez Gene)
GRB2GeneProduct2885 (Entrez Gene)
HSPA1AGeneProduct3303 (Entrez Gene)
HSPA5GeneProduct3309 (Entrez Gene)
HSPA8GeneProduct3312 (Entrez Gene)
HSPB1GeneProduct3315 (Entrez Gene)
HSPB2GeneProduct3316 (Entrez Gene)
IKBKBGeneProduct3551 (Entrez Gene)
IKBKGGeneProduct8517 (Entrez Gene)
IL1AGeneProduct3552 (Entrez Gene)
IL1BGeneProduct3553 (Entrez Gene)
IL1R1GeneProduct3554 (Entrez Gene)
IL1R2GeneProduct7850 (Entrez Gene)
JUNGeneProduct3725 (Entrez Gene)
JUNDGeneProduct3727 (Entrez Gene)
KRASGeneProduct3845 (Entrez Gene)
LRRK2-mutGeneProduct120892 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP2K1IP1GeneProduct8649 (Entrez Gene)
MAP2K2GeneProduct5605 (Entrez Gene)
MAP2K4GeneProduct6416 (Entrez Gene)
MAP2K5GeneProduct5607 (Entrez Gene)
MAP2K6GeneProduct5608 (Entrez Gene)
MAP2K7GeneProduct5609 (Entrez Gene)
MAP3K11GeneProduct4296 (Entrez Gene)
MAP3K12GeneProduct7786 (Entrez Gene)
MAP3K13GeneProduct9175 (Entrez Gene)
MAP3K1GeneProduct4214 (Entrez Gene)
MAP3K14GeneProduct9020 (Entrez Gene)
MAP3K4GeneProduct4216 (Entrez Gene)
MAP3K5GeneProduct4217 (Entrez Gene)
MAP3K6GeneProduct9064 (Entrez Gene)
MAP3K7GeneProduct6885 (Entrez Gene)
MAP3K7IP1GeneProduct10454 (Entrez Gene)
MAP3K7IP2GeneProduct23118 (Entrez Gene)
MAP3K8GeneProduct1326 (Entrez Gene)
MAP4K1GeneProduct11184 (Entrez Gene)
MAP4K3GeneProduct8491 (Entrez Gene)
MAP4K4GeneProduct9448 (Entrez Gene)
MAPK10GeneProduct5602 (Entrez Gene)
MAPK12GeneProduct6300 (Entrez Gene)
MAPK13GeneProduct5603 (Entrez Gene)
MAPK14GeneProduct1432 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
MAPK4GeneProduct5596 (Entrez Gene)
MAPK6GeneProduct5597 (Entrez Gene)
MAPK7GeneProduct5598 (Entrez Gene)
MAPK8GeneProduct5599 (Entrez Gene)
MAPK8IP3GeneProduct23162 (Entrez Gene)
MAPK9GeneProduct5601 (Entrez Gene)
MAPKAPK2GeneProduct9261 (Entrez Gene)
MAPKAPK5GeneProduct8550 (Entrez Gene)
MAPTGeneProduct4137 (Entrez Gene)
MAXGeneProduct4149 (Entrez Gene)
MEF2CGeneProduct4208 (Entrez Gene)
MEKK2/3GeneProduct171492 (Entrez Gene)
MINK1GeneProduct50488 (Entrez Gene)
MOSGeneProduct4342 (Entrez Gene)
MRASGeneProduct22808 (Entrez Gene)
MYCGeneProduct4609 (Entrez Gene)
NF1GeneProduct4763 (Entrez Gene)
NFKB1GeneProduct4790 (Entrez Gene)
NGFBGeneProduct4803 (Entrez Gene)
NLKGeneProduct51701 (Entrez Gene)
NR4A1GeneProduct3164 (Entrez Gene)
NRASGeneProduct4893 (Entrez Gene)
NTF5GeneProduct4909 (Entrez Gene)
NTRK1GeneProduct4914 (Entrez Gene)
PAK1GeneProduct5058 (Entrez Gene)
PAK2GeneProduct5062 (Entrez Gene)
PDGFBGeneProduct5155 (Entrez Gene)
PDGFRBGeneProduct5159 (Entrez Gene)
PLA2G10GeneProduct8399 (Entrez Gene)
PLA2G5GeneProduct5322 (Entrez Gene)
PPM1AGeneProduct5494 (Entrez Gene)
PPM1BGeneProduct5495 (Entrez Gene)
PPP3CAGeneProduct5530 (Entrez Gene)
PPP3CBGeneProduct5532 (Entrez Gene)
PPP3CCGeneProduct5533 (Entrez Gene)
PPP3R1GeneProduct5534 (Entrez Gene)
PPP3R2GeneProduct5535 (Entrez Gene)
PPP5CGeneProduct5536 (Entrez Gene)
PRKACAGeneProduct5566 (Entrez Gene)
PRKCB1GeneProduct5579 (Entrez Gene)
PRKCDGeneProduct5580 (Entrez Gene)
PRKCGGeneProduct5582 (Entrez Gene)
PRKCHGeneProduct5583 (Entrez Gene)
PRKCZGeneProduct5590 (Entrez Gene)
PTPN5GeneProduct84867 (Entrez Gene)
PTPN7GeneProduct5778 (Entrez Gene)
PTPRRGeneProduct5801 (Entrez Gene)
Phosphatidylinositol signaling systemPathway
RAC1GeneProduct5879 (Entrez Gene)
RAC2GeneProduct5880 (Entrez Gene)
RAF1GeneProduct5894 (Entrez Gene)
RAP1AGeneProduct5906 (Entrez Gene)
RAP1BGeneProduct5908 (Entrez Gene)
RASA1GeneProduct5921 (Entrez Gene)
RASA2GeneProduct5922 (Entrez Gene)
RASGRF2GeneProduct5924 (Entrez Gene)
RASGRP1GeneProduct10125 (Entrez Gene)
RASGRP4GeneProduct115727 (Entrez Gene)
RPS6KA3GeneProduct6197 (Entrez Gene)
SITPECGeneProduct51295 (Entrez Gene)
SOS2GeneProduct6655 (Entrez Gene)
SRFGeneProduct6722 (Entrez Gene)
STK3GeneProduct6788 (Entrez Gene)
STMN1GeneProduct3925 (Entrez Gene)
TAOK1GeneProduct57551 (Entrez Gene)
TAOK2GeneProduct9344 (Entrez Gene)
TGFB1GeneProduct7040 (Entrez Gene)
TGFB2GeneProduct7042 (Entrez Gene)
TGFB3GeneProduct7043 (Entrez Gene)
TGFBR1GeneProduct7046 (Entrez Gene)
TGFBR2GeneProduct7048 (Entrez Gene)
TMEM37GeneProduct140738 (Entrez Gene)
TNFGeneProduct7124 (Entrez Gene)
TP53GeneProduct7157 (Entrez Gene)
TRAF2GeneProduct7186 (Entrez Gene)
TRAF6GeneProduct7189 (Entrez Gene)
VemurafenibMetabolite24747352 (Chemspider)
Wnt signaling pathwayPathwayWP428
ZAKGeneProduct51776 (Entrez Gene)
cAMPMetaboliteHMDB00058 (HMDB)
p53 signaling pathwayPathway

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