KEGG   PATHWAY: ko04010Help
Entry
ko04010                     Pathway                                

Name
MAPK signaling pathway
Description
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.
Class
09130 Environmental Information Processing; 09132 Signal transduction
BRITE hierarchy
Pathway map
ko04010  MAPK signaling pathway
ko04010

Ortholog table
Module
M00687  MAPK (ERK1/2) signaling [PATH:ko04010]
M00688  MAPK (JNK) signaling [PATH:ko04010]
M00689  MAPK (p38) signaling [PATH:ko04010]
M00690  MAPK (ERK5) signaling [PATH:ko04010]
Disease
H00078  Frontotemporal lobar degeneration (FTLD)
H00265  Hereditary sensory and autonomic neuropathy (HSAN)
H00484  Multiple synostosis syndrome
H00505  FGFR3-related short limb skeletal dysplasia
H00523  Noonan syndrome and related disorders
H00532  Parkes Weber syndrome
H00540  Osteoporosis, lymphedema, anhydrotic ectodermal dysplasia with immunodeficiency (OLEDAID)
H00574  Coffin-Lowry syndrome (CLS)
H00595  Myofibrillar myopathies (MFM)
H00642  Lacrimo-auriculo-dento-digital syndrome (LADD)
H00645  Incontinentia pigmenti
H00677  Aplasia of lacrimal and salivary glands
H00728  Brugada syndrome (BRS)
H00746  Hypokalemic periodic paralysis (HypoPP)
H00749  Episodic ataxias
H00775  Familial or sporadic hemiplegic migraine
H00787  Congenital stationary night blindness (CSNB)
H00800  Loeys-Dietz syndrome (LDS)
H00801  Familial thoracic aortic aneurysm and dissection (TAAD)
H00808  Idiopathic generalized epilepsies (IGEs)
H00881  Li-Fraumeni syndrome
H00882  Cocoon syndrome
H00894  FG syndrome (FGS)
H00912  Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
H00916  Congenital central hypoventilation syndrome (CCHS)
H00997  CATSHL syndrome
H01007  Choroid plexus papilloma
H01193  Familial tumoral calcinosis (FTC)
H01207  Trigonocephaly
H01250  Hereditary gingival fibromatosis (HGF)
H01276  Chronic idiopathic intestinal pseudo-obstruction
H01385  Rienhoff syndrome
H01437  Neurofibromatosis type 1
H01512  Langerhans cell histiocytosis
H01738  Noonan syndrome
H01745  Cardiofaciocutaneous syndrome
H01905  Trichomegaly
H01984  Leopard syndrome
H02043  Capillary malformation-arteriovenous malformation
H02064  Atelosteogenesis type I and III
H02067  Boomerang dysplasia
H02068  Hypochondroplasia
H02069  SADDAN
Other DBs
BSID: 456
GO: 0000165
Orthology
K04344  voltage-dependent calcium channel P/Q type alpha-1A
K04849  voltage-dependent calcium channel N type alpha-1B
K04850  voltage-dependent calcium channel L type alpha-1C
K04851  voltage-dependent calcium channel L type alpha-1D
K04852  voltage-dependent calcium channel R type alpha-1E
K04853  voltage-dependent calcium channel L type alpha-1F
K04854  voltage-dependent calcium channel T type alpha-1G
K04855  voltage-dependent calcium channel T type alpha-1H
K04856  voltage-dependent calcium channel T type alpha-1I
K04857  voltage-dependent calcium channel L type alpha-1S
K04858  voltage-dependent calcium channel alpha-2/delta-1
K04859  voltage-dependent calcium channel alpha-2/delta-2
K04860  voltage-dependent calcium channel alpha-2/delta-3
K04861  voltage-dependent calcium channel alpha-2/delta-4
K04862  voltage-dependent calcium channel beta-1
K04863  voltage-dependent calcium channel beta-2
K04864  voltage-dependent calcium channel beta-3
K04865  voltage-dependent calcium channel beta-4
K04866  voltage-dependent calcium channel gamma-1
K04867  voltage-dependent calcium channel gamma-2
K04868  voltage-dependent calcium channel gamma-3
K04869  voltage-dependent calcium channel gamma-4
K04870  voltage-dependent calcium channel gamma-5
K04871  voltage-dependent calcium channel gamma-6
K04872  voltage-dependent calcium channel gamma-7
K04873  voltage-dependent calcium channel gamma-8
K04345  protein kinase A [EC:2.7.11.11]
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K19663  classical protein kinase C gamma type [EC:2.7.11.13]
K04346  guanine nucleotide-binding protein subunit alpha-12
K04347  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K04349  Ras-specific guanine nucleotide-releasing factor 1
K12326  Ras-specific guanine nucleotide-releasing factor 2
K04350  RAS guanyl-releasing protein 1
K12361  RAS guanyl-releasing protein 2
K12362  RAS guanyl-releasing protein 3
K12363  RAS guanyl-releasing protein 4
K08018  Rap guanine nucleotide exchange factor 2
K08052  neurofibromin 1
K04352  Ras GTPase-activating protein 1
K08053  Ras GTPase-activating protein 2
K04353  Ras-related protein Rap-1A
K07836  Ras-related protein Rap-1B
K04357  epidermal growth factor
K08774  transforming growth factor, alpha
K09784  epiregulin
K09782  amphiregulin
K18496  fibroblast growth factor 1
K18497  fibroblast growth factor 2
K04358  fibroblast growth factor
K22603  fibroblast growth factor 19
K22429  fibroblast growth factor 21
K22428  fibroblast growth factor 23
K05451  nerve growth factor, alpha
K02582  nerve growth factor, beta
K04355  brain-derived neurotrophic factor
K04356  neurotrophin 3
K12457  neurotrophin 4
K04526  insulin
K05459  insulin-like growth factor 1
K13769  insulin-like growth factor 2
K04359  platelet-derived growth factor subunit A
K17386  platelet-derived growth factor subunit B
K05450  platelet derived growth factor C/D
K05453  macrophage colony-stimulating factor 1
K05461  KIT ligand
K05454  fms-related tyrosine kinase 3 ligand
K05448  vascular endothelial growth factor A
K16858  vascular endothelial growth factor B
K16859  placenta growth factor
K05449  vascular endothelial growth factor C/D
K05460  hepatocyte growth factor
K05465  angiopoietin 1
K05466  angiopoietin 2
K05467  angiopoietin 4
K05462  ephrin-A
K04361  epidermal growth factor receptor [EC:2.7.10.1]
K05083  receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1]
K05084  receptor tyrosine-protein kinase erbB-3 [EC:2.7.10.1]
K05085  receptor tyrosine-protein kinase erbB-4 [EC:2.7.10.1]
K04362  fibroblast growth factor receptor 1 [EC:2.7.10.1]
K05093  fibroblast growth factor receptor 2 [EC:2.7.10.1]
K05094  fibroblast growth factor receptor 3 [EC:2.7.10.1]
K05095  fibroblast growth factor receptor 4 [EC:2.7.10.1]
K02583  tumor necrosis factor receptor superfamily member 16
K03176  neurotrophic tyrosine kinase receptor type 1 [EC:2.7.10.1]
K04360  neurotrophic tyrosine kinase receptor type 2 [EC:2.7.10.1]
K04527  insulin receptor [EC:2.7.10.1]
K05087  insulin-like growth factor 1 receptor [EC:2.7.10.1]
K04363  platelet-derived growth factor receptor alpha [EC:2.7.10.1]
K05089  platelet-derived growth factor receptor beta [EC:2.7.10.1]
K05090  macrophage colony-stimulating factor 1 receptor [EC:2.7.10.1]
K05091  proto-oncogene tyrosine-protein kinase Kit [EC:2.7.10.1]
K05092  fms-related tyrosine kinase 3 [EC:2.7.10.1]
K05096  FMS-like tyrosine kinase 1 [EC:2.7.10.1]
K05097  FMS-like tyrosine kinase 4 [EC:2.7.10.1]
K05098  kinase insert domain protein receptor [EC:2.7.10.1]
K05099  proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1]
K05121  endothelial-specific receptor tyrosine kinase [EC:2.7.10.1]
K05103  Eph receptor A2 [EC:2.7.10.1]
K04364  growth factor receptor-binding protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K07829  Ras-related protein R-Ras
K07830  Ras-related protein R-Ras2
K07831  Ras-related protein M-Ras
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04370  ragulator complex protein LAMTOR3
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04372  MAP kinase interacting serine/threonine kinase [EC:2.7.11.1]
K04373  ribosomal protein S6 kinase alpha-1/2/3/6 [EC:2.7.11.1]
K04374  cyclic AMP-dependent transcription factor ATF-4
K04375  ETS domain-containing protein Elk-1
K04376  ETS domain-containing protein Elk-4
K04377  Myc proto-oncogene protein
K04378  serum response factor
K04379  proto-oncogene protein c-fos
K04380  microtubule-associated protein tau
K04381  stathmin
K16342  cytosolic phospholipase A2 [EC:3.1.1.4]
K03156  tumor necrosis factor superfamily, member 2
K04383  interleukin 1 alpha
K04519  interleukin 1 beta
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K03158  tumor necrosis factor receptor superfamily member 1A
K04386  interleukin 1 receptor type I
K04723  interleukin 1 receptor accessory protein
K04674  TGF-beta receptor type-1 [EC:2.7.11.30]
K04388  TGF-beta receptor type-2 [EC:2.7.11.30]
K04389  tumor necrosis factor ligand superfamily member 6
K04390  tumor necrosis factor receptor superfamily member 6
K04391  monocyte differentiation antigen CD14
K04392  Ras-related C3 botulinum toxin substrate 1
K07860  Ras-related C3 botulinum toxin substrate 2
K07861  Ras-related C3 botulinum toxin substrate 3
K04393  cell division control protein 42
K03171  tumor necrosis factor receptor type 1-associated DEATH domain protein
K02187  caspase 3 [EC:3.4.22.56]
K03173  TNF receptor-associated factor 2 [EC:2.3.2.27]
K02308  death-associated protein 6
K04729  myeloid differentiation primary response protein MyD88
K04730  interleukin-1 receptor-associated kinase 1 [EC:2.7.11.1]
K04733  interleukin-1 receptor-associated kinase 4 [EC:2.7.11.1]
K03175  TNF receptor-associated factor 6 [EC:2.3.2.27]
K04402  growth arrest and DNA-damage-inducible protein
K04403  TAK1-binding protein 1
K04404  TAK1-binding protein 2
K04405  evolutionarily conserved signaling intermediate in Toll pathway
K04406  mitogen-activated protein kinase kinase kinase kinase 3 [EC:2.7.11.1]
K04407  mitogen-activated protein kinase kinase kinase kinase 4 [EC:2.7.11.1]
K04408  mitogen-activated protein kinase kinase kinase kinase 1 [EC:2.7.11.1]
K04409  p21-activated kinase 1 [EC:2.7.11.1]
K04410  p21-activated kinase 2 [EC:2.7.11.1]
K04411  serine/threonine kinase 4
K04412  serine/threonine kinase 3
K04414  mitogen-activated protein kinase kinase kinase kinase 2 [EC:2.7.11.1]
K04415  mitogen-activated protein kinase kinase kinase 8 [EC:2.7.11.25]
K04416  mitogen-activated protein kinase kinase kinase 1 [EC:2.7.11.25]
K04419  mitogen-activated protein kinase kinase kinase 11 [EC:2.7.11.25]
K04420  mitogen-activated protein kinase kinase kinase 2 [EC:2.7.11.25]
K04421  mitogen-activated protein kinase kinase kinase 3 [EC:2.7.11.25]
K04422  mitogen-activated protein kinase kinase kinase 13 [EC:2.7.11.25]
K04423  mitogen-activated protein kinase kinase kinase 12 [EC:2.7.11.25]
K04424  sterile alpha motif and leucine zipper containing kinase AZK [EC:2.7.11.25]
K04425  mitogen-activated protein kinase kinase kinase 6 [EC:2.7.11.25]
K04426  mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25]
K04427  mitogen-activated protein kinase kinase kinase 7 [EC:2.7.11.25]
K04428  mitogen-activated protein kinase kinase kinase 4 [EC:2.7.11.25]
K04429  thousand and one amino acid protein kinase [EC:2.7.11.1]
K04430  mitogen-activated protein kinase kinase 4 [EC:2.7.12.2]
K04431  mitogen-activated protein kinase kinase 7 [EC:2.7.12.2]
K04432  mitogen-activated protein kinase kinase 3 [EC:2.7.12.2]
K04433  mitogen-activated protein kinase kinase 6 [EC:2.7.12.2]
K04434  mitogen-activated protein kinase 8 interacting protein 1
K04435  mitogen-activated protein kinase 8 interacting protein 2
K04436  mitogen-activated protein kinase 8 interacting protein 3
K04437  filamin
K04438  proto-oncogene C-crk
K04439  beta-arrestin
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04441  p38 MAP kinase [EC:2.7.11.24]
K04442  mitogen-activated protein kinase-activated protein kinase 5 [EC:2.7.11.1]
K04443  mitogen-activated protein kinase-activated protein kinase 2 [EC:2.7.11.1]
K04444  mitogen-activated protein kinase-activated protein kinase 3 [EC:2.7.11.1]
K04445  ribosomal protein S6 kinase alpha-5 [EC:2.7.11.1]
K16510  ribosomal protein S6 kinase alpha-4 [EC:2.7.11.1]
K05866  M-phase inducer phosphatase 2 [EC:3.1.3.48]
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17333  nuclear factor of activated T-cells, cytoplasmic 3
K04448  transcription factor AP-1
K04449  transcription factor jun-D
K04450  cyclic AMP-dependent transcription factor ATF-2
K04451  tumor protein p53
K04452  DNA damage-inducible transcript 3
K04453  Max protein
K04454  MADS-box transcription enhancer factor 2C
K04455  heat shock protein beta-1
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04457  protein phosphatase 1A [EC:3.1.3.16]
K04458  receptor-type tyrosine-protein phosphatase R [EC:3.1.3.48]
K18018  tyrosine-protein phosphatase non-receptor type 5 [EC:3.1.3.48]
K18019  tyrosine-protein phosphatase non-receptor type 7 [EC:3.1.3.48]
K21278  dual specificity protein phosphatase 1 [EC:3.1.3.48 3.1.3.16]
K04459  dual specificity MAP kinase phosphatase [EC:3.1.3.48 3.1.3.16]
K21946  dual specificity phosphatase 6 [EC:3.1.3.48 3.1.3.16]
K18498  dual specificity phosphatase 9 [EC:3.1.3.48 3.1.3.16]
K20216  dual specificity phosphatase 10 [EC:3.1.3.48 3.1.3.16]
K17614  dual specificity phosphatase 3 [EC:3.1.3.48 3.1.3.16]
K04460  serine/threonine-protein phosphatase 5 [EC:3.1.3.16]
K04461  protein phosphatase 1B [EC:3.1.3.16]
K03283  heat shock 70kDa protein 1/2/6/8
K04462  ecotropic virus integration site 1 protein
K04463  mitogen-activated protein kinase kinase 5 [EC:2.7.12.2]
K04464  mitogen-activated protein kinase 7 [EC:2.7.11.24]
K04465  nuclear receptor subfamily 4 group A member 1
K04466  mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K04468  nemo like kinase [EC:2.7.11.24]
K02580  nuclear factor NF-kappa-B p105 subunit
K04469  nuclear factor of kappa light polypeptide gene enhancer in B-cells 2
K04735  transcription factor p65
K09253  transcription factor RelB
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00338  Lipopolysaccharide
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
  Authors
Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH.
  Title
MAP kinases.
  Journal
Chem Rev 101:2449-76 (2001)
DOI:10.1021/cr000241p
Reference
  Authors
Tanoue T, Nishida E.
  Title
Docking interactions in the mitogen-activated protein kinase cascades.
  Journal
Pharmacol Ther 93:193-202 (2002)
DOI:10.1016/S0163-7258(02)00188-2
Reference
  Authors
Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S.
  Title
MAPK pathways in radiation responses.
  Journal
Oncogene 22:5885-96 (2003)
DOI:10.1038/sj.onc.1206701
Reference
  Authors
Huang EJ, Reichardt LF.
  Title
Trk receptors: roles in neuronal signal transduction.
  Journal
Annu Rev Biochem 72:609-42 (2003)
DOI:10.1146/annurev.biochem.72.121801.161629
Reference
  Authors
Harper SJ, LoGrasso P.
  Title
Signalling for survival and death in neurones: the role of stress-activated kinases, JNK and p38.
  Journal
Cell Signal 13:299-310 (2001)
DOI:10.1016/S0898-6568(01)00148-6
Reference
  Authors
Takeda K, Ichijo H
  Title
Neuronal p38 MAPK signalling: an emerging regulator of cell fate and function in the nervous system.
  Journal
Genes Cells 7:1099-111 (2002)
DOI:10.1046/j.1365-2443.2002.00591.x
Reference
  Authors
Yang SH, Sharrocks AD, Whitmarsh AJ.
  Title
Transcriptional regulation by the MAP kinase signaling cascades.
  Journal
Gene 320:3-21 (2003)
DOI:10.1016/S0378-1119(03)00816-3
Reference
  Authors
Zhu X, Lee HG, Raina AK, Perry G, Smith MA.
  Title
The role of mitogen-activated protein kinase pathways in Alzheimer's disease.
  Journal
Neurosignals 11:270-81 (2002)
DOI:10.1159/000067426
Reference
  Authors
Cho H, Lee J, Kwak NJ, Lee KH, Rha S, Kim YH, Cho YY, Yang KH, Kim K, Lim Y.
  Title
Silica induces nuclear factor-kappaB activation through TAK1 and NIK in Rat2 cell line.
  Journal
Toxicol Lett 143:323-30 (2003)
DOI:10.1016/S0378-4274(03)00193-0
Reference
  Authors
Lemmon MA, Schlessinger J
  Title
Cell signaling by receptor tyrosine kinases.
  Journal
Cell 141:1117-34 (2010)
DOI:10.1016/j.cell.2010.06.011
Reference
  Authors
Skaper SD
  Title
The neurotrophin family of neurotrophic factors: an overview.
  Journal
Methods Mol Biol 846:1-12 (2012)
DOI:10.1007/978-1-61779-536-7_1
Reference
  Authors
Chu WM
  Title
Tumor necrosis factor.
  Journal
Cancer Lett 328:222-5 (2013)
DOI:10.1016/j.canlet.2012.10.014
Reference
  Authors
Newton K, Dixit VM
  Title
Signaling in innate immunity and inflammation.
  Journal
Cold Spring Harb Perspect Biol 4:a006049 (2012)
DOI:10.1101/cshperspect.a006049
Reference
  Authors
Gaestel M, Kotlyarov A, Kracht M
  Title
Targeting innate immunity protein kinase signalling in inflammation.
  Journal
Nat Rev Drug Discov 8:480-99 (2009)
DOI:10.1038/nrd2829
Reference
  Authors
Ajibade AA, Wang HY, Wang RF
  Title
Cell type-specific function of TAK1 in innate immune signaling.
  Journal
Trends Immunol 34:307-16 (2013)
DOI:10.1016/j.it.2013.03.007
Reference
  Authors
Turner MD, Nedjai B, Hurst T, Pennington DJ
  Title
Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease.
  Journal
Biochim Biophys Acta 1843:2563-2582 (2014)
DOI:10.1016/j.bbamcr.2014.05.014
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