RAF/MAP kinase cascade (Homo sapiens)

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2, 366114, 56611p21 RAS nucleoplasmActivated RAF1 complex p21 RAS p21 RASGTP p21 RAS p21 RAS Activated RAF1 complex p21 RASGTP Activated RAF1 complex phospho-ERK-1 dimer p21 RASGTP phospho-ERK-1MEK1 p21 RASGTP RASRAF MEK2ERK-2 Activated RAF1 complex phospho-ERK-1 dimer Activated RAF1 complexMEK RASRAF14-3-3 p21 RAS MEK1ERK-1 RASRAF RasGTPp-Raf1p21 RAS p21 RAS phospho-ERK-2 dimer p-Raf1p21 RAS p21 RASGTP cytosolp21 RASGTP p21 RASGTP MEK Activated RAF1 complex phospho-ERK-2MEK2 phospho-ERK-2 dimer HRASGTP HRASGTP Activated RAF1 complexMEK2 Activated RAF1 complexMEK1 p21 RASGTP ADPMAP2K2 p-S259,Y340,Y341,S621-RAF1 Activated RAF1 complexMEKp-S259,S621-RAF1 phospho-ERK-2 dimerKRASKRASGTP p-S259,S621-RAF1 NRAS YWHABp-T202,Y204-MAPK3 GTP unidentified protein tyrosine kinasep-S259,Y340,Y341,S621-RAF1 RasGTPp-Raf1ADPHRASGTP p-S259,Y340,Y341,S621-RAF1 ATPKRASHRASHRASGTPATPNRAS YWHABphospho-ERK-1MEK1NRAS p-S218,S222-MAP2K1 YWHABNRAS GTP Activated RAF1 complexHRASATPp-S218,S222-MAP2K1 NRAS YWHABATPMEK1GTP Activated RAF1 complexMAPK1HRASMEK2ERK-2MEK1ERK-1NRAS ATPMAP2K2 p-S259,S621-RAF1 p-T185,Y187-MAPK1 phospho-ERK-1 dimerActivated RAF1 complexMEK1GTP phospho-ERK-2MEK2KRASp-T185,Y187-MAPK1 HRASYWHABYWHABp-T202,Y204-MAPK3p-S,T-MAP2K2 p-S259,S621-RAF1YWHABMAP2K1 phospho-ERK-1 dimerYWHABMAPK3p-Raf1KRASActivated RAF1 complexMEK2GTP KRASp-S259,Y340,Y341,S621-RAF1 RASRAF14-3-3HRASKRASp-S259,S621-RAF1 p-S,T-MAP2K2phospho-ERK-2 dimerMEKHRASp-S218,S222-MAP2K1ADPADPp-MEK1p-S,T-MAP2K2 HRASGTP RASRAFp-T161-CDK1MAPK3 p-T202,Y204-MAPK3 p-S259,Y340,Y341,S621-RAF1 HRASMAP2K1 p-T185,Y187-MAPK1MAPK1 p-T185,Y187-MAPK1 KRASHRASGTP GTP p-T202,Y204-MAPK3 p21 RASGTPADPNRAS NRAS


Description

The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=109869

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Bibliography

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  366. Boga SB, Deng Y, Zhu L, Nan Y, Cooper AB, Shipps GW, Doll R, Shih NY, Zhu H, Sun R, Wang T, Paliwal S, Tsui HC, Gao X, Yao X, Desai J, Wang J, Alhassan AB, Kelly J, Patel M, Muppalla K, Gudipati S, Zhang LK, Buevich A, Hesk D, Carr D, Dayananth P, Black S, Mei H, Cox K, Sherborne B, Hruza AW, Xiao L, Jin W, Long B, Liu G, Taylor SA, Kirschmeier P, Windsor WT, Bishop R, Samatar AA.; ''MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.''; PubMed Europe PMC Scholia
  367. Luo X, Feng L, Jiang X, Xiao F, Wang Z, Feng GS, Chen Y.; ''Characterization of the topology and functional domains of RKTG.''; PubMed Europe PMC Scholia
  368. Prior IA, Lewis PD, Mattos C.; ''A comprehensive survey of Ras mutations in cancer.''; PubMed Europe PMC Scholia
  369. Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K.; ''Purification and characterization of human Syk produced using a baculovirus expression system.''; PubMed Europe PMC Scholia
  370. Herbst RS.; ''Review of epidermal growth factor receptor biology.''; PubMed Europe PMC Scholia
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  374. Chen RH, Sarnecki C, Blenis J.; ''Nuclear localization and regulation of erk- and rsk-encoded protein kinases.''; PubMed Europe PMC Scholia
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  381. Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMed Europe PMC Scholia
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  385. McGillicuddy LT, Fromm JA, Hollstein PE, Kubek S, Beroukhim R, De Raedt T, Johnson BW, Williams SM, Nghiemphu P, Liau LM, Cloughesy TF, Mischel PS, Parret A, Seiler J, Moldenhauer G, Scheffzek K, Stemmer-Rachamimov AO, Sawyers CL, Brennan C, Messiaen L, Mellinghoff IK, Cichowski K.; ''Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.''; PubMed Europe PMC Scholia
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  388. King PD, Lubeck BA, Lapinski PE.; ''Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis.''; PubMed Europe PMC Scholia
  389. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114761view16:25, 25 January 2021ReactomeTeamReactome version 75
113205view11:27, 2 November 2020ReactomeTeamReactome version 74
112429view15:37, 9 October 2020ReactomeTeamReactome version 73
101333view11:22, 1 November 2018ReactomeTeamreactome version 66
100871view20:55, 31 October 2018ReactomeTeamreactome version 65
100412view19:28, 31 October 2018ReactomeTeamreactome version 64
99961view16:13, 31 October 2018ReactomeTeamreactome version 63
99516view14:46, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99158view12:41, 31 October 2018ReactomeTeamreactome version 62
93933view13:46, 16 August 2017ReactomeTeamreactome version 61
93520view11:25, 9 August 2017ReactomeTeamreactome version 61
88127view10:15, 26 July 2016RyanmillerOntology Term : 'kinase mediated signaling pathway' added !
88126view10:15, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86618view09:22, 11 July 2016ReactomeTeamreactome version 56
83142view10:09, 18 November 2015ReactomeTeamVersion54
81486view13:01, 21 August 2015ReactomeTeamVersion53
76963view08:24, 17 July 2014ReactomeTeamFixed remaining interactions
76668view12:03, 16 July 2014ReactomeTeamFixed remaining interactions
75998view10:05, 11 June 2014ReactomeTeamRe-fixing comment source
75701view11:04, 10 June 2014ReactomeTeamReactome 48 Update
75057view13:56, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74701view08:46, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated RAF1 complex MEK1ComplexREACT_4256 (Reactome)
Activated RAF1 complex MEK2ComplexREACT_4223 (Reactome)
Activated RAF1 complex MEKComplexREACT_3953 (Reactome)
Activated RAF1 complexComplexREACT_4906 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
HRAS GTPComplexREACT_24217 (Reactome)
HRASProteinP01112 (Uniprot-TrEMBL)
KRASProteinP01116 (Uniprot-TrEMBL)
MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
MAP2K2 ProteinP36507 (Uniprot-TrEMBL)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK1ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPK3ProteinP27361 (Uniprot-TrEMBL)
MEK1 ERK-1ComplexREACT_5539 (Reactome)
MEK1REACT_2607 (Reactome)
MEK2 ERK-2ComplexREACT_5435 (Reactome)
MEKProteinREACT_2275 (Reactome)
NRAS ProteinP01111 (Uniprot-TrEMBL)
RAS

RAF

14-3-3
ComplexREACT_3642 (Reactome)
RAS RAFComplexREACT_3036 (Reactome)
Ras

GTP

p-Raf1
ComplexREACT_24177 (Reactome)
YWHABProteinP31946 (Uniprot-TrEMBL)
p-MEK1ProteinREACT_3339 (Reactome)
p-Raf1ComplexREACT_4612 (Reactome)
p-S,T-MAP2K2 ProteinP36507 (Uniprot-TrEMBL)
p-S,T-MAP2K2ProteinP36507 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1 ProteinQ02750 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1ProteinQ02750 (Uniprot-TrEMBL)
p-S259,S621-RAF1 ProteinP04049 (Uniprot-TrEMBL)
p-S259,S621-RAF1ProteinP04049 (Uniprot-TrEMBL)
p-S259,Y340,Y341,S621-RAF1 ProteinP04049 (Uniprot-TrEMBL)
p-T161-CDK1ProteinP06493 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3ProteinP27361 (Uniprot-TrEMBL)
p21 RAS GTPComplexREACT_4782 (Reactome)
phospho-ERK-1 MEK1ComplexREACT_2796 (Reactome)
phospho-ERK-1 dimerComplexREACT_3152 (Reactome)
phospho-ERK-1 dimerComplexREACT_3932 (Reactome)
phospho-ERK-2 MEK2ComplexREACT_3199 (Reactome)
phospho-ERK-2 dimerComplexREACT_3688 (Reactome)
phospho-ERK-2 dimerComplexREACT_5046 (Reactome)
unidentified protein tyrosine kinaseREACT_4938 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_136 (Reactome)
ADPArrowREACT_1727 (Reactome)
ADPArrowREACT_1836 (Reactome)
ADPArrowREACT_2247 (Reactome)
ADPArrowREACT_525 (Reactome)
ADPArrowREACT_545 (Reactome)
ATPREACT_136 (Reactome)
ATPREACT_1727 (Reactome)
ATPREACT_1836 (Reactome)
ATPREACT_2247 (Reactome)
ATPREACT_525 (Reactome)
ATPREACT_545 (Reactome)
Activated RAF1 complex MEK1REACT_545 (Reactome)
Activated RAF1 complex MEK2REACT_1727 (Reactome)
Activated RAF1 complex MEKmim-catalysisREACT_1727 (Reactome)
Activated RAF1 complex MEKmim-catalysisREACT_545 (Reactome)
Activated RAF1 complexArrowREACT_1727 (Reactome)
Activated RAF1 complexArrowREACT_525 (Reactome)
Activated RAF1 complexArrowREACT_545 (Reactome)
Activated RAF1 complexREACT_143 (Reactome)
HRAS GTPREACT_23877 (Reactome)
MAPK1REACT_495 (Reactome)
MAPK3REACT_1780 (Reactome)
MEK1 ERK-1REACT_136 (Reactome)
MEK1 ERK-1mim-catalysisREACT_136 (Reactome)
MEK1REACT_1836 (Reactome)
MEK2 ERK-2REACT_2247 (Reactome)
MEK2 ERK-2mim-catalysisREACT_2247 (Reactome)
MEKREACT_143 (Reactome)
RAS

RAF

14-3-3
REACT_525 (Reactome)
RAS RAFArrowREACT_359 (Reactome)
RAS RAFREACT_996 (Reactome)
REACT_1019 (Reactome) MEK2 dissociates from phospho-ERK2, allowing phospho-ERK2 to dimerise with another phospho-ERK2.
REACT_1289 (Reactome) Two phospho-ERK1 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets.
REACT_136 (Reactome) MEK1 phosphorylates the critical Tyrosine and Threonine on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity.
REACT_143 (Reactome) MEK-1/2 have a proline rich domain (P) and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells.
MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP.
REACT_1727 (Reactome) Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
REACT_1740 (Reactome) MEK1 dissociates from phospho-ERK1, allowing phospho-ERK1 to dimerise with another phospho-ERK1.
REACT_1780 (Reactome) In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y).
REACT_1836 (Reactome) At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'MEK1' are present. At the end of this reaction, 1 molecule of 'phospho_MEK1', and 2 molecules of 'ADP' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'protein serine/threonine kinase activity' of 'phospho-Cdc2 (Thr 161)'.

REACT_1866 (Reactome) Phospho-ERK-1 dimer is translocated from cytosol to nucleoplasm.
REACT_2158 (Reactome) Inactive Raf-1 is associated in the cytoplasm with 14-3-3. 14-3-3 binds to Raf-1 via the Ser259 phosphorylation site (S1). This interaction stabilises the inactive conformation of Raf-1 in which the Ras-binding Cysteine-rich domain (CRD) is obscured. The Raf-1 molecule contains an additional p21ras-binding domain (RBD), a second serine phosphorylation site at S621 (S2) and two tyrosine phosphorylation sites (at 340, Y1 and 341, Y2).
REACT_2196 (Reactome) Two phospho-ERK2 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets.
REACT_2247 (Reactome) MEK2 phosphorylates the critical Tyrosine and Threonine on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity.
REACT_23877 (Reactome) A key event for Ras transformation involves the direct physical association between Ras and the Raf-1 kinase. This interaction promotes both Raf translocation to the plasma membrane and activation of Raf kinase activity.
REACT_359 (Reactome) Activated p21ras (the GTP-bound form) is associated with the plasma membrane. Inactive Raf-1 is associated in the cytoplasm with 14-3-3. 14-3-3 binds to Raf-1 via the Ser259 phosphorylation site (S1). This interaction stabilises the inactive conformation of Raf-1 in which the Ras-binding Cysteine-rich domain (CRD) is obscured. The Raf-1 molecule contains an additional p21ras-binding domain (RBD), a second serine phosphorylation site at S621 (S2) and two tyrosine phosphorylation sites (at 340, Y1 and 341, Y2).
Raf-1 binds activated p21ras via the RBD. This displaces 14-3-3 from Ser259 and unmasks the CRD.
REACT_487 (Reactome) Phospho-ERK-2 dimer is translocated from cytosol to nucleoplasm.
REACT_495 (Reactome) In the cytoplasm activated MEK2 (Serine phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T183) and a critical Tyrosine (Y185).
REACT_525 (Reactome) An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341 (Y1, Y2 in diagram) of Raf-1. This serves to further stabilise the active 'open' Raf-1 conformation. While the kinase has not been definitively identified, Src is a plausible candidate: coexpression of Raf-1 and Src in Sf9 cells resulted in phosphorylation of Y340/Y341 and enzymatic activationof Raf-1; Raf-1 interacts with Src and co-immunoprecipitates with Src/Fyn in NIH-3T3 cells.
REACT_545 (Reactome) Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
REACT_996 (Reactome) 14-3-3 has been displaced from Ser259. 14-3-3 may now bind its higher affinity Ser621 (S2) site. This stabilises an 'open' Raf-1 conformation that is catalytically active, and bound to p21ras via both p21ras-binding domains, CRD and RBD.
YWHABArrowREACT_359 (Reactome)
YWHABREACT_2158 (Reactome)
YWHABREACT_996 (Reactome)
p-MEK1ArrowREACT_1836 (Reactome)
p-MEK1TBarREACT_136 (Reactome)
p-Raf1REACT_359 (Reactome)
p-S,T-MAP2K2ArrowREACT_1019 (Reactome)
p-S,T-MAP2K2ArrowREACT_1727 (Reactome)
p-S,T-MAP2K2REACT_495 (Reactome)
p-S218,S222-MAP2K1ArrowREACT_1740 (Reactome)
p-S218,S222-MAP2K1ArrowREACT_545 (Reactome)
p-S218,S222-MAP2K1REACT_1780 (Reactome)
p-S259,S621-RAF1REACT_2158 (Reactome)
p-S259,S621-RAF1REACT_23877 (Reactome)
p-T161-CDK1mim-catalysisREACT_1836 (Reactome)
p-T185,Y187-MAPK1ArrowREACT_1019 (Reactome)
p-T202,Y204-MAPK3ArrowREACT_1740 (Reactome)
p21 RAS GTPREACT_359 (Reactome)
phospho-ERK-1 MEK1ArrowREACT_136 (Reactome)
phospho-ERK-2 MEK2ArrowREACT_2247 (Reactome)
unidentified protein tyrosine kinasemim-catalysisREACT_525 (Reactome)
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