Signaling by NTRK1 (Homo sapiens)

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4, 10, 19, 2524, 2612921, 24, 2617122018322236271623211214723p-SHC beta-NGF homodimer AP-2 complex p21 RASGTP Activated TrkA receptor complexClathrin-coated vesicle Phospho-IRS1/2 MAP kinase p38 beta-NGF homodimer beta-NGF homodimer ARMSCrk PI3K-catalytic subunit AP-2 complex Phospho-B-Raf GRB2SOSPhospho-SHC beta-NGF homodimer PI3K beta-NGF homodimer B-Raf complex B-RAF p21 RAS Adaptor protein complex 2 Activated TrkA receptor complex Clathrin-coated vesicle AP-2 complex RALA-GDP Activated TrkA receptor complexClathrin-coated vesicledyneindynactin complex Phospho-IRS1/2PI3Kp21 RAS Phospho-IRS1/2 Clathrin-coated vesicle Activated TrkA receptor complex Activated TrkA receptor complex RIT/RIN-GDP Active TrkA receptorPhospho-ARMSCrkC3G complex endosomeRALA-GDP beta-NGF homodimer Activated TrkA receptor complex PI3K-regulatory subunit RIT/RIN-GTP RIT/RIN RALB-GDP PI3K-regulatory subunit Active TrkA receptorPhospho-PLCG1 complex B-Raf complex Activated TrkA receptor complex Active TrkA receptor complexRIT/RIN-GDP Activated TrkA receptor complexClathrin-coated vesicleEndophilin Rap1-GDP Clathrin-coated vesicle Adaptor protein complex 2 Activated TrkA receptor complex Activated TrkA receptorPhospho-IRS1/2 RALB-GDP Active TrkAPhospho-ARMSCrkC3GRap1-GTP complex Rap1-GTP B-Raf complex PACAPPACAP type 1 receptor RAL-GTP Activated TrkA receptorIRS1/2 Rap1-GTPB-Raf complex Clathrin Activated TrkA receptorPhospho-IRS1/2PI3KPI3K-catalytic subunit Activated TrkA receptor complex Activated TrkA receptor complex Ras-GTPRalGDS complex Activated TrkA receptor complex beta-NGF homodimer beta-NGF dimerTrkA receptor dimer Rap1-GTP B-RAF RIT/RIN PI3K-catalytic subunit Rap1-GTP beta-NGF homodimer beta-NGF homodimer beta-NGF homodimer Active TrkA receptorp-FRS2CRKL complex beta-NGF homodimer Phospho-ARMSCrk Active TrkA receptorPhospho-ARMSCrk complex MAP kinase p38 Adaptor protein complex 2 Activated TrkA receptor complex Active Trk receptor complexRIT/RIN-GTP IRS1,2 Activated TrkA receptor complex RIT/RIN-GDP mature beta-NGF homodimer PP2A-ABdeltaC complex RALB-GTP beta-NGF homodimer beta-NGF dimerTrkA receptor Activated TrkA receptor complex Activated TrkA receptorp-SHC Active TrkA receptorFRS2 complex Phospho-ARMSCrk Clathrin RIT/RIN PI3K-regulatory subunit Active TrkA receptorPhospho-Frs2CrkLC3G complex PIP3RhoA RAL-GDP clathrin-coated endocytic vesicleClathrin RAL-GDP Activated TrkA receptorSHC nucleoplasmp21 RAS Activated TrkA receptor complex RALA-GTP Activated TrkA receptor complex beta-NGF homodimer Active TrkA receptorFRS2 complex beta-NGF homodimer Active TrkA receptorPhospho-ARMSCrkC3G complex PI3K ARMSCrk AP-2 complex Activated TrkA receptor complex p21 RASGTP beta-NGF homodimer GRB2SOS1 Activated TrkA receptor complex RIT/RIN Activated TrkA receptor complex p21 RAS beta-NGF homodimer beta-NGF homodimer beta-NGF homodimer Activated TrkA receptor complex Rap1-GTP Activated TrkA receptor complex beta-NGF homodimer beta-NGF homodimer p21 RASGDP beta-NGF homodimer p-SHC Active Trk receptor complexRIT/RIN-GTPB-RAF Rap1-GDP Phospho-MAP kinase p38 beta-NGF homodimer Active TrkA receptorPhospho-ARMSCrkC3G complex AdenosineAdenosine A2a receptor beta-NGF homodimer Activated TrkA receptor complex Clathrin beta-NGF homodimer Activated TrkA receptor complex Activated TrkA receptor complex Adaptor protein complex 2 Active TrkAPhospho-ARMSCrkC3GRap1Phospho-B-Raf complex beta-NGF homodimer Activated TrkA receptor complex Golgi lumenActivated TrkA receptor complex beta-NGF homodimer Activated TrkA receptor complex GRB2SOS1 beta-NGF homodimer RIT/RIN-GTP beta-NGF homodimer beta-NGF homodimer p21 RASGTP Phospho-ARMSCrk Activated TrkA receptor complex Phospho-ARMSCrk Phospho-p38 MAPK alpha/beta PI3K Clathrin-coated vesicle Phospho-IRS1/2 SHC Active TrkA receptorARMSCrk complex cytosolbeta-NGF homodimer beta-NGF homodimer Active TrkA receptorPLCG1 complex Active TrkA receptorp-FRS2 complex AP2B1 PiCRKL Phospho-ERK dimerCRKL RHOA NGF Phospho-Ribosomal protein S6 kinaseGTP NRAS p-6Y-FRS2ADORA2APIActive TrkA receptorARMSCrk complexAP2S1 RIT2 ATPp-Y-SHC3 Ade-Rib IRS1 NGF H2OHRASActivated TrkA receptorIRS1/2KRASRIT1 SHC2 NGF AP2S1 p-5Y-NTRK1 Active Trk receptor complexRIT/RIN-GTPNGF Intracellular Trk receptorATPNGF p-5Y-NTRK1 BRAF ADPGTP PIK3R2 AP2A2RALA CLTA p-5Y-NTRK1 NGF ATPp-5Y-NTRK1 p-5Y-NTRK1 AP2A1 Activated TrkA receptor complexKRASGTP beta-NGF dimerTrkA receptor dimerAP2A1 Active Trk receptor complexRIT/RIN-GTPB-RAFRAF/MAP kinase cascadeMAPK13 p-5Y-NTRK1-1 RALGDS PP2A-ABdeltaC complexRap1-GTPB-Raf complexGTPNGF Rap1-GTPPIK3R1 mature beta-NGF homodimerp-4Y-PLCG1 RAP1A AP2M1 Active TrkA receptorp-FRS2 complexGDP NRAS p-Y-SHC2 Activated TrkA receptor complexGTPATPGRB2-1 Mg2+ p-Y-SHC3 Active TrkAPhospho-ARMSCrkC3GRap1Phospho-B-Raf complexMAPK7AP2B1 DNAL4p-S63-ATF1Active TrkA receptorFRS2 complexActivated TrkA receptorPhospho-IRS1/2PI3KAP2A1 p-Y-IRS2 Zn2+ NGF p-Y1096-KIDINS220 AP2M1 p-5Y-NTRK1-1 ADPp21 RASGTPGDPNRAS Rap1-GDPELK1NGF CLTA RALGDSp-T218,Y220-MAPK7CRKLActive TrkA receptor complexRIT/RIN-GDPNGF PIK3CB p21 RASGTPAP2M1 Activated TrkA receptor complexClathrin-coated vesicledyneindynactin complexActivated TrkA receptorPhospho-IRS1/2ADPADCYAP1R1NGF Activated TrkA receptor complexp-Y-SHC2 MAPKAP kinaseRIT2 RAL-GTPAP2M1 GRB2-1 RIT/RIN-GDPGDP Activated TrkA receptor complexRAP1A SH3GL2GDP RIT2 Mg2+ NTRK1 NGF p-Y-SHC1 MAPK12 CRKPIP3 activates AKT signalingGTP Zn2+ ATPRap1-GTPRAP1A FRS2p-5Y-NTRK1 GTP ADCYAP1p-5Y-NTRK1 RALB p-5Y-NTRK1 p-4S,T336-ELK1NGF ATPPIK3CB RALA SOS1 p-5Y-NTRK1 ADPp-Y-IRS1 YWHABPiH2OB-RAFATPFRS2p-6Y-FRS2ATPNGF RAPGEF1 Dynamin-1/2/3NGF p-5Y-NTRK1-1 p-Y-IRS1 AP2A2GDP PLCG1PLCG1BRAF p-S133-CREB1NGF NGF GTP NGF p-MAPK p38 alpha/betaGDPNGF CRKActivated TrkA receptorp-SHCp-Y419-SRC-1Active TrkA receptorPhospho-ARMSCrkC3G complexZn2+ ATPActive MAPKAP kinaseMEF2MAP kinase p38 p-S212,S360,S376,T581-RPS6KA5KRASRALA AP2B1 MAPK14 Rap1-GDPAde-RibActive TrkA receptorPLCG1 complexIntracellular Phosphorylated Trk receptorsp-5Y-NTRK1 p-Y-IRS1 p-5Y-NTRK1 p-5Y-NTRK1-1 IRS1,2GDPGTP YWHABBRAF NGF Zn2+ HRASB-Raf complexGuanine nucleotide exchange factorGTP RHOAATPRIT1 HRASCRKBRAF IRS2 p-5Y-NTRK1 CRKFRS2KIDINS220 p-5Y-NTRK1 GTP Activated TrkA receptor complexPhospho-MEF2GDPGDPH2OATPp-Y1096-KIDINS220 p-SHCPIP3 p-5Y-NTRK1 ADPNTRK1Zn2+ PIK3CA GTPGTPRIT2 SHC3 NGF p-5Y-NTRK1 RIT1 p-Y1096-KIDINS220 GTP RAF/MAP kinase cascadeRibosomal protein S6 kinaseNTRK1 GTP SH3GL2 RAPGEF1PIK3R2 Clathrin-coated vesicleActive TrkAPhospho-ARMSCrkC3GRap1-GTP complexRALB p-5Y-NTRK1 p-Y-SHC1 PIK3CA ADPARMSCrkp-5Y-NTRK1 ATF1PIK3R1 NGF p-Y-IRS2 Active TrkA receptorPhospho-Frs2CrkLC3G complexPACAPPACAP type 1 receptorATPp-T218,Y220-MAPK7Activated TrkA receptor complexClathrin-coated vesiclep-T180,Y182-MAPK14 MAP2K5BRAF CRKYWHABp-5Y-NTRK1 beta-NGF dimerTrkA receptorp-5Y-NTRK1 MAPK11 AP2B1 PIK3CA ADPp-Y1096-KIDINS220 ADPGTPRAP1A p-5Y-NTRK1-1 ADPSOS1 GDPPIKRASRas-GTPRalGDS complexAP2A1 RAP1A RAP1A PPP2R5D NGF RALB SHCATPSRC-1CLTA ADPPIK3R1 p-S727-STAT3p-6Y-FRS2GRB2SOSPhospho-SHCp-S,T-BRAF Activated TrkA receptor complexClathrin-coated vesicleEndophilinCLTA Phospho-IRS1/2PI3Kp-4Y-PLCG1RAL-GDPGDP AP2A2ERK1/2/5PIK3CB CRKADCYAP1NGF PI3KAP2S1 ERK-specific DUSPKIDINS220 HRASRAP1A p-T180,Y182-MAPK11 p-5Y-NTRK1-1 Activated TrkA receptor complexADPNGF GRB2SOS1GDP AdenosineAdenosine A2a receptorZn2+ Phospho-MAP kinase p38 RAF/MAP kinase cascadeActivated TrkA receptorSHCRAL-GDPADPATPADPp-Y-IRS2 PIK3R2 ADORA2A RPS6KA5NGF NGF NGF ADPActive TrkA receptorPhospho-PLCG1 complexActive TrkA receptorFRS2 complexAP2S1 STAT3PIP3RhoANGF Active TrkA receptorp-FRS2CRKL complexADCYAP1R1 p-5Y-NTRK1 NGF NGF ATPActive TrkA receptorPhospho-ARMSCrk complexp-ERK1/2/5RIT1 p21 RASGDPp-5Y-NTRK1 p-T222,S272-MAPKAPK2AP2A2ADPGDP PiNRAS GTPYWHABSHC1 B-Raf complexCREB1SH3GL2 p-5Y-NTRK1 NGF DAG and IP3 signalingp-5Y-NTRK1 5, 158, 135, 155, 1511


Description

Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=187037

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History

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CompareRevisionActionTimeUserComment
123615view08:20, 7 August 2022EgonwModified title
115037view16:57, 25 January 2021ReactomeTeamReactome version 75
113481view11:55, 2 November 2020ReactomeTeamReactome version 74
112680view16:07, 9 October 2020ReactomeTeamReactome version 73
101597view11:46, 1 November 2018ReactomeTeamreactome version 66
101133view21:31, 31 October 2018ReactomeTeamreactome version 65
100661view20:05, 31 October 2018ReactomeTeamreactome version 64
100211view16:50, 31 October 2018ReactomeTeamreactome version 63
99762view15:16, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93968view13:48, 16 August 2017ReactomeTeamreactome version 61
93566view11:27, 9 August 2017ReactomeTeamreactome version 61
88055view13:48, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86668view09:23, 11 July 2016ReactomeTeamreactome version 56
83147view10:09, 18 November 2015ReactomeTeamVersion54
81496view13:02, 21 August 2015ReactomeTeamVersion53
76973view08:26, 17 July 2014ReactomeTeamFixed remaining interactions
76678view12:04, 16 July 2014ReactomeTeamFixed remaining interactions
76006view10:06, 11 June 2014ReactomeTeamRe-fixing comment source
75713view11:06, 10 June 2014ReactomeTeamReactome 48 Update
75066view13:57, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74710view08:47, 30 April 2014ReactomeTeamReactome46
69004view17:46, 8 July 2013MaintBotUpdated to 2013 gpml schema
42091view21:56, 4 March 2011MaintBotAutomatic update
39899view05:55, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADCYAP1ProteinP18509 (Uniprot-TrEMBL)
ADCYAP1R1 ProteinP41586 (Uniprot-TrEMBL)
ADCYAP1R1ProteinP41586 (Uniprot-TrEMBL)
ADORA2A ProteinP29274 (Uniprot-TrEMBL)
ADORA2AProteinP29274 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AP2A1 ProteinO95782 (Uniprot-TrEMBL)
AP2A2ProteinO94973 (Uniprot-TrEMBL)
AP2B1 ProteinP63010 (Uniprot-TrEMBL)
AP2M1 ProteinQ96CW1 (Uniprot-TrEMBL)
AP2S1 ProteinP53680 (Uniprot-TrEMBL)
ARMS CrkComplexREACT_12089 (Reactome)
ATF1ProteinP18846 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TrkA receptor IRS1/2ComplexREACT_13110 (Reactome)
Activated TrkA receptor

Phospho-IRS1/2

PI3K		ComplexREACT_12678 (Reactome)
Activated TrkA receptor Phospho-IRS1/2ComplexREACT_13002 (Reactome)
Activated TrkA receptor SHCComplexREACT_12103 (Reactome)
Activated TrkA receptor p-SHCComplexREACT_12114 (Reactome)
Activated TrkA receptor complex

Clathrin-coated vesicle

Endophilin		ComplexREACT_13349 (Reactome)
Activated TrkA receptor complex

Clathrin-coated vesicle dynein

dynactin complex		ComplexREACT_13375 (Reactome)
Activated TrkA receptor complex Clathrin-coated vesicleComplexREACT_13141 (Reactome)
Activated TrkA receptor complexComplexREACT_10696 (Reactome)
Activated TrkA receptor complexComplexREACT_10757 (Reactome)
Active MAPKAP kinaseProteinREACT_12330 (Reactome)
Active Trk receptor complex

RIT/RIN-GTP

B-RAF		ComplexREACT_12347 (Reactome)
Active Trk receptor complex RIT/RIN-GTPComplexREACT_12211 (Reactome)
Active TrkA

Phospho-ARMS Crk C3G Rap1

Phospho-B-Raf complex		ComplexREACT_12169 (Reactome)
Active TrkA

Phospho-ARMS Crk C3G

Rap1-GTP complex		ComplexREACT_12359 (Reactome)
Active TrkA receptor

ARMS

Crk complex		ComplexREACT_12251 (Reactome)
Active TrkA receptor FRS2 complexComplexREACT_12147 (Reactome)
Active TrkA receptor PLCG1 complexComplexREACT_12180 (Reactome)
Active TrkA receptor

Phospho-ARMS Crk

C3G complex		ComplexREACT_12225 (Reactome)
Active TrkA receptor

Phospho-ARMS

Crk complex		ComplexREACT_12282 (Reactome)
Active TrkA receptor

Phospho-Frs2 CrkL

C3G complex		ComplexREACT_12337 (Reactome)
Active TrkA receptor Phospho-PLCG1 complexComplexREACT_12153 (Reactome)
Active TrkA receptor

p-FRS2

CRKL complex		ComplexREACT_12126 (Reactome)
Active TrkA receptor p-FRS2 complexComplexREACT_12171 (Reactome)
Active TrkA receptor complex RIT/RIN-GDPComplexREACT_12112 (Reactome)
Ade-Rib MetaboliteCHEBI:16335 (ChEBI)
Ade-RibMetaboliteCHEBI:16335 (ChEBI)
Adenosine Adenosine A2a receptorComplexREACT_11028 (Reactome)
B-RAFComplexREACT_12124 (Reactome)
B-Raf complexComplexREACT_12219 (Reactome)
B-Raf complexComplexREACT_12300 (Reactome)
BRAF ProteinP15056 (Uniprot-TrEMBL)
CLTA ProteinP09496 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
CRKL ProteinP46109 (Uniprot-TrEMBL)
CRKLProteinP46109 (Uniprot-TrEMBL)
CRKProteinP46108 (Uniprot-TrEMBL)
Clathrin-coated vesicleComplexREACT_13103 (Reactome)
DAG and IP3 signalingPathwayREACT_111064 (Reactome) This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
DNAL4ProteinO96015 (Uniprot-TrEMBL)
Dynamin-1/2/3REACT_22651 (Reactome)
ELK1ProteinP19419 (Uniprot-TrEMBL)
ERK-specific DUSPREACT_12976 (Reactome)
ERK1/2/5ProteinREACT_13316 (Reactome)
FRS2ProteinQ8WU20 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2

SOS

Phospho-SHC		ComplexREACT_2380 (Reactome)
GRB2 SOS1ComplexREACT_4435 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Guanine nucleotide exchange factorREACT_12202 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRASProteinP01112 (Uniprot-TrEMBL)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS1,2ProteinREACT_12744 (Reactome) The proteins mentioned here are examples of IRS family members acting as indicated for IRS. More family members are to be confirmed and added in the future.
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
Intracellular Phosphorylated Trk receptorsProteinREACT_10421 (Reactome)
Intracellular Trk receptorProteinREACT_10478 (Reactome)
KIDINS220 ProteinQ9ULH0 (Uniprot-TrEMBL)
KRASProteinP01116 (Uniprot-TrEMBL)
MAP kinase p38 ComplexREACT_12099 (Reactome)
MAP2K5ProteinQ13163 (Uniprot-TrEMBL)
MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
MAPK12 ProteinP53778 (Uniprot-TrEMBL)
MAPK13 ProteinO15264 (Uniprot-TrEMBL)
MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
MAPK7ProteinQ13164 (Uniprot-TrEMBL)
MAPKAP kinaseProteinREACT_12293 (Reactome)
MEF2ProteinREACT_13049 (Reactome)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NGF ProteinP01138 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NTRK1 ProteinP04629 (Uniprot-TrEMBL)
NTRK1ProteinP04629 (Uniprot-TrEMBL)
PACAP PACAP type 1 receptorComplexREACT_10139 (Reactome)
PI3KComplexREACT_4240 (Reactome)
PIMetaboliteCHEBI:16618 (ChEBI)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIP3 RhoAComplexREACT_12649 (Reactome)
PIP3 MetaboliteCHEBI:16618 (ChEBI)
PIP3 activates AKT signalingPathwayREACT_75829 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PP2A-ABdeltaC complexComplexREACT_2369 (Reactome)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
Phospho-ERK dimerREACT_12827 (Reactome)
Phospho-IRS1/2 PI3KComplexREACT_12858 (Reactome)
Phospho-MAP kinase p38 ComplexREACT_12273 (Reactome)
Phospho-MEF2ProteinREACT_12996 (Reactome)
Phospho-Ribosomal protein S6 kinaseProteinREACT_12696 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAF/MAP kinase cascadePathwayREACT_634 (Reactome) 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.
RAL-GDPComplexREACT_12274 (Reactome)
RAL-GTPComplexREACT_12304 (Reactome)
RALA ProteinP11233 (Uniprot-TrEMBL)
RALB ProteinP11234 (Uniprot-TrEMBL)
RALGDS ProteinQ12967 (Uniprot-TrEMBL)
RALGDSProteinQ12967 (Uniprot-TrEMBL)
RAP1A ProteinP62834 (Uniprot-TrEMBL)
RAPGEF1 ProteinQ13905 (Uniprot-TrEMBL)
RAPGEF1ProteinQ13905 (Uniprot-TrEMBL)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOAProteinP61586 (Uniprot-TrEMBL)
RIT/RIN-GDPComplexREACT_12139 (Reactome)
RIT1 ProteinQ92963 (Uniprot-TrEMBL)
RIT2 ProteinQ99578 (Uniprot-TrEMBL)
RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
Rap1-GDPComplexREACT_12111 (Reactome)
Rap1-GDPComplexREACT_12289 (Reactome)
Rap1-GTP B-Raf complexComplexREACT_12223 (Reactome)
Rap1-GTPComplexREACT_12189 (Reactome)
Rap1-GTPComplexREACT_12362 (Reactome)
Ras-GTP RalGDS complexComplexREACT_12340 (Reactome)
Ribosomal protein S6 kinaseProteinREACT_13229 (Reactome)
SH3GL2 ProteinQ99962 (Uniprot-TrEMBL)
SH3GL2ProteinQ99962 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC2 ProteinP98077 (Uniprot-TrEMBL)
SHC3 ProteinQ92529 (Uniprot-TrEMBL)
SHCProteinREACT_12338 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
STAT3ProteinP40763 (Uniprot-TrEMBL)
YWHABProteinP31946 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
beta-NGF dimer TrkA receptor dimerComplexREACT_10135 (Reactome)
beta-NGF dimer TrkA receptorComplexREACT_10893 (Reactome)
mature beta-NGF homodimerComplexREACT_10239 (Reactome)
p-4S,T336-ELK1ProteinP19419 (Uniprot-TrEMBL)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG1ProteinP19174 (Uniprot-TrEMBL)
p-5Y-NTRK1 ProteinP04629 (Uniprot-TrEMBL)
p-5Y-NTRK1-1 ProteinP04629-1 (Uniprot-TrEMBL)
p-6Y-FRS2ProteinQ8WU20 (Uniprot-TrEMBL)
p-ERK1/2/5ProteinREACT_13301 (Reactome)
p-MAPK p38 alpha/betaProteinREACT_12925 (Reactome)
p-S,T-BRAF ProteinP15056 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S212,S360,S376,T581-RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
p-S63-ATF1ProteinP18846 (Uniprot-TrEMBL)
p-S727-STAT3ProteinP40763 (Uniprot-TrEMBL)
p-SHCProteinREACT_12146 (Reactome)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T218,Y220-MAPK7ProteinQ13164 (Uniprot-TrEMBL)
p-T222,S272-MAPKAPK2ProteinP49137 (Uniprot-TrEMBL)
p-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y-SHC2 ProteinP98077 (Uniprot-TrEMBL)
p-Y-SHC3 ProteinQ92529 (Uniprot-TrEMBL)
p-Y1096-KIDINS220 ProteinQ9ULH0 (Uniprot-TrEMBL)
p-Y419-SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
p21 RAS GDPComplexREACT_2657 (Reactome)
p21 RAS GTPComplexREACT_4782 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADCYAP1R1REACT_10128 (Reactome)
ADCYAP1R1mim-catalysisREACT_10128 (Reactome)
ADCYAP1REACT_10128 (Reactome)
ADORA2AREACT_9980 (Reactome)
ADORA2Amim-catalysisREACT_9980 (Reactome)
ADPArrowREACT_12016 (Reactome)
ADPArrowREACT_12032 (Reactome)
ADPArrowREACT_12057 (Reactome)
ADPArrowREACT_12063 (Reactome)
ADPArrowREACT_12066 (Reactome)
ADPArrowREACT_12075 (Reactome)
ADPArrowREACT_12406 (Reactome)
ADPArrowREACT_12413 (Reactome)
ADPArrowREACT_12434 (Reactome)
ADPArrowREACT_12437 (Reactome)
ADPArrowREACT_12487 (Reactome)
ADPArrowREACT_12546 (Reactome)
ADPArrowREACT_12576 (Reactome)
ADPArrowREACT_12586 (Reactome)
ADPArrowREACT_12622 (Reactome)
ADPArrowREACT_12624 (Reactome)
ADPArrowREACT_12631 (Reactome)
ADPArrowREACT_9962 (Reactome)
ARMS CrkREACT_11996 (Reactome)
ATF1REACT_12437 (Reactome)
ATPREACT_12016 (Reactome)
ATPREACT_12032 (Reactome)
ATPREACT_12057 (Reactome)
ATPREACT_12063 (Reactome)
ATPREACT_12066 (Reactome)
ATPREACT_12075 (Reactome)
ATPREACT_12406 (Reactome)
ATPREACT_12413 (Reactome)
ATPREACT_12434 (Reactome)
ATPREACT_12437 (Reactome)
ATPREACT_12487 (Reactome)
ATPREACT_12546 (Reactome)
ATPREACT_12576 (Reactome)
ATPREACT_12586 (Reactome)
ATPREACT_12622 (Reactome)
ATPREACT_12624 (Reactome)
ATPREACT_12631 (Reactome)
ATPREACT_9962 (Reactome)
Activated TrkA receptor IRS1/2REACT_12434 (Reactome)
Activated TrkA receptor IRS1/2mim-catalysisREACT_12434 (Reactome)
Activated TrkA receptor Phospho-IRS1/2ArrowREACT_12434 (Reactome)
Activated TrkA receptor Phospho-IRS1/2REACT_12384 (Reactome)
Activated TrkA receptor SHCmim-catalysisREACT_12003 (Reactome)
Activated TrkA receptor complex

Clathrin-coated vesicle

Endophilin		ArrowREACT_12397 (Reactome)
Activated TrkA receptor complex Clathrin-coated vesicleREACT_12397 (Reactome)
Activated TrkA receptor complexArrowREACT_12019 (Reactome)
Activated TrkA receptor complexArrowREACT_12061 (Reactome)
Activated TrkA receptor complexArrowREACT_9962 (Reactome)
Activated TrkA receptor complexREACT_11996 (Reactome)
Activated TrkA receptor complexREACT_11998 (Reactome)
Activated TrkA receptor complexREACT_12010 (Reactome)
Activated TrkA receptor complexREACT_12017 (Reactome)
Activated TrkA receptor complexREACT_12036 (Reactome)
Activated TrkA receptor complexREACT_12502 (Reactome)
Activated TrkA receptor complexREACT_12559 (Reactome)
Activated TrkA receptor complexmim-catalysisREACT_12057 (Reactome)
Active MAPKAP kinaseArrowREACT_12032 (Reactome)
Active Trk receptor complex RIT/RIN-GTPArrowREACT_12071 (Reactome)
Active Trk receptor complex RIT/RIN-GTPREACT_12000 (Reactome)
Active TrkA

Phospho-ARMS Crk C3G Rap1

Phospho-B-Raf complex		ArrowREACT_12046 (Reactome)
Active TrkA

Phospho-ARMS Crk C3G

Rap1-GTP complex		REACT_12046 (Reactome)
Active TrkA receptor

ARMS

Crk complex		REACT_12066 (Reactome)
Active TrkA receptor

ARMS

Crk complex		mim-catalysisREACT_12066 (Reactome)
Active TrkA receptor FRS2 complexREACT_12063 (Reactome)
Active TrkA receptor PLCG1 complexmim-catalysisREACT_12063 (Reactome)
Active TrkA receptor

Phospho-ARMS Crk

C3G complex		mim-catalysisREACT_12037 (Reactome)
Active TrkA receptor

Phospho-ARMS

Crk complex		ArrowREACT_12066 (Reactome)
Active TrkA receptor

Phospho-Frs2 CrkL

C3G complex		mim-catalysisREACT_12083 (Reactome)
Active TrkA receptor

p-FRS2

CRKL complex		REACT_12015 (Reactome)
Active TrkA receptor p-FRS2 complexArrowREACT_12063 (Reactome)
Active TrkA receptor p-FRS2 complexREACT_12023 (Reactome)
Active TrkA receptor complex RIT/RIN-GDPREACT_12071 (Reactome)
Ade-RibREACT_9980 (Reactome)
Adenosine Adenosine A2a receptorArrowREACT_9980 (Reactome)
B-RAFREACT_12000 (Reactome)
B-Raf complexREACT_12046 (Reactome)
B-Raf complexREACT_12050 (Reactome)
CREB1REACT_12586 (Reactome)
CREB1REACT_12622 (Reactome)
CREB1REACT_12631 (Reactome)
CRKLREACT_12023 (Reactome)
Clathrin-coated vesicleREACT_12559 (Reactome)
DNAL4mim-catalysisREACT_12385 (Reactome)
Dynamin-1/2/3mim-catalysisREACT_12397 (Reactome)
ELK1REACT_12406 (Reactome)
ERK-specific DUSPmim-catalysisREACT_12439 (Reactome)
ERK1/2/5ArrowREACT_12439 (Reactome)
ERK1/2/5ArrowREACT_12539 (Reactome)
FRS2REACT_12010 (Reactome)
GDPArrowREACT_12037 (Reactome)
GDPArrowREACT_12041 (Reactome)
GDPArrowREACT_12071 (Reactome)
GDPArrowREACT_12083 (Reactome)
GDPArrowREACT_12397 (Reactome)
GDPArrowREACT_2010 (Reactome)
GRB2

SOS

Phospho-SHC		mim-catalysisREACT_2010 (Reactome)
GRB2 SOS1REACT_176 (Reactome)
GTPREACT_12037 (Reactome)
GTPREACT_12041 (Reactome)
GTPREACT_12071 (Reactome)
GTPREACT_12083 (Reactome)
GTPREACT_12397 (Reactome)
GTPREACT_2010 (Reactome)
Guanine nucleotide exchange factormim-catalysisREACT_12071 (Reactome)
H2OREACT_12397 (Reactome)
H2OREACT_12439 (Reactome)
H2OREACT_12539 (Reactome)
IRS1,2REACT_12502 (Reactome)
Intracellular Phosphorylated Trk receptorsArrowREACT_10128 (Reactome)
Intracellular Phosphorylated Trk receptorsArrowREACT_9980 (Reactome)
Intracellular Trk receptorREACT_10128 (Reactome)
Intracellular Trk receptorREACT_9980 (Reactome)
MAP kinase p38 REACT_12016 (Reactome)
MAP2K5mim-catalysisREACT_12075 (Reactome)
MAPK7REACT_12075 (Reactome)
MAPKAP kinaseREACT_12032 (Reactome)
MEF2REACT_12413 (Reactome)
NTRK1REACT_10014 (Reactome)
NTRK1REACT_10088 (Reactome)
PACAP PACAP type 1 receptorArrowREACT_10128 (Reactome)
PI3KREACT_12384 (Reactome)
PIArrowREACT_12624 (Reactome)
PIREACT_12577 (Reactome)
PIREACT_12624 (Reactome)
PLCG1REACT_11998 (Reactome)
PP2A-ABdeltaC complexmim-catalysisREACT_12539 (Reactome)
Phospho-ERK dimermim-catalysisREACT_12406 (Reactome)
Phospho-ERK dimermim-catalysisREACT_12576 (Reactome)
Phospho-IRS1/2 PI3Kmim-catalysisREACT_12624 (Reactome)
Phospho-MAP kinase p38 ArrowREACT_12016 (Reactome)
Phospho-MAP kinase p38 mim-catalysisREACT_12032 (Reactome)
Phospho-MEF2ArrowREACT_12413 (Reactome)
Phospho-Ribosomal protein S6 kinaseArrowREACT_12487 (Reactome)
Phospho-Ribosomal protein S6 kinasemim-catalysisREACT_12622 (Reactome)
PiArrowREACT_12397 (Reactome)
PiArrowREACT_12439 (Reactome)
PiArrowREACT_12539 (Reactome)
RAL-GDPArrowREACT_12030 (Reactome)
RAL-GDPREACT_12041 (Reactome)
RAL-GTPArrowREACT_12041 (Reactome)
RAL-GTPREACT_12030 (Reactome)
RAL-GTPmim-catalysisREACT_12030 (Reactome)
RALGDSREACT_12001 (Reactome)
RAPGEF1REACT_12015 (Reactome)
REACT_10014 (Reactome) The binding of neurotrotrophin to TrkA receptors induce their dimerization to form receptor homodimers.
REACT_10033 (Reactome) TRKA at the plasma membrane typically results in rapid endocytosis and subsequent passage of the receptors through a network of endosomal compartments.
REACT_10088 (Reactome) Neurotrophin dimer binding to TRK receptors causes receptor dimerization. Although the dissociation constants of NGF for TRK and p75NTR are very similar, the binding kinetics are quite different: NGF associates with and dissociates from p75NTR much more rapidly than from TRKA. p75NTR regulates the affinity and specificity of TRK receptor activation by neurotrophins is regulated. Its presence is required to observe high affinity binding to TRK receptors, since it increases the rate of neurotrophin association with TRK proteins. The major ligand binding domain in TRK receptors is the membrane-proximal Ig-C2-like domain (named Ig2 domain or domain 5), although other regions in in the TRK extracellular domains are also important for ligand binding.
The N termini of neurotrophins are important in controlling binding specificity, and the structure of this region is reorganized upon binding to a TRK receptor. In some neurons, TRK receptors are localized to intracellular vesicles in the absence of signals. Electrical activity, cAMP, and Ca2+ stimulate TRK insertion into the cell surface by exocytosis of cytoplasmic membrane vesicles containing TRK. At axon terminals, TRK receptors undergo ligand-dependent endocytosis upon ligand binding. The internalized neurotrophin-TRK complex is then sorted and enters either recycling or retrograde transport pathways.

REACT_10128 (Reactome) Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that acts through type 1 PACAP receptor, a G protein-coupled receptor. PACAP exerts its trophic effects using TrkA receptors and utilizing tyrosine kinase signaling pathways. The mechanism of activation is still poorly understood.
REACT_11995 (Reactome) C3G is a guanine nucleotide exchange factor for Rap1, which is recruited by Crk adaptor proteins.
REACT_11996 (Reactome) Ankyrin-Rich Membrane Spanning protein (ARMS or Kidins220) is a specific target of Trk receptor tyrosine phosphorylation. The ARMS/Kidins220:Crk complex is an upstream component of the C3G-Rap1-MAP kinase cascade and is SH3 dependent.
REACT_11998 (Reactome) The PLC-gamma 1 docking site in Trk receptor (Y785) is important for initiation and maintenance of hippocampal LTP (long term potentiation); this residue in TrkA receptor also binds to CHK tyrosine kinase, which participates in MAPK pathway activation and is involved in PC12 cells neurite outgrowth in response to NGF. PLC-gamma 1 activation results in long term induction of a sodium channel gene (PN1).
REACT_12000 (Reactome) Once activated by RIT or RIN, B-RAF activates, through MEK, the p38 MAP kinase. Whereas RIN appears to activate p38 (specifically the p38-alpha isoform) but not the ERKs, RIN was described to activate ERK1/ ERK2 as well, although to a much lower extent than p38. RIN signaling gives rise to sustained activation of p38 MAP kinase.
REACT_12001 (Reactome) Besides the RAF kinase, RAS can activate several ral guanine nucleotide dissociation stimulators (RALGDSs). Binding of RALGDS with RAS competes with RAF binding to RAS.
REACT_12003 (Reactome) Phosphorylation of Shc adapter proteins, and the concomitant recruitment of GRB2/SOS, results in the RAS-dependent, transient activation of ERKs, which is correlated with mitogenic and proliferative cell signalling. Prolonged activation of ERKs is instead regulated by a parallel pathway, involving CRK/C3G-dependent activation of the RAS-like GTPase RAP-1, and takes place in early endosomes.
REACT_12010 (Reactome) FRS2 binds to TRKA through the same motif (NPXY) around the TRKA phospho-tyrosine residue Y496 to which SHC proteins bind. The competition between SHC proteins and FRS2 for binding to NGF-activated TRKA may provide a novel mechanism by which proliferation and differentiation may be regulated in response to neurotrophin stimulation. Tyrosine phosphorylation of FRS2 occurs within 2 min of NGF stimulation.
REACT_12015 (Reactome) C3G is a guanine nucleotide exchange factor for Rap1, which is recruited by Crk adaptor proteins.
REACT_12016 (Reactome) The NGF activation of p38 MAP kinase is transient, being maximal at 10 min and declining to near control levels by 30 min. T180 and Y182 are two sites that become newly phosphorylated as p38 MAPK becomes activated.
REACT_12017 (Reactome) SHC proteins (SHC 1, 2, 3) are signalling adapters, able to interact with phosphorylated Y496 of TRKA. SHC2 and SHC3 appear to be the primary SHC adaptor proteins in neurons as they are expressed in both the developing and adult nervous system. SHC1 is expressed embryonically but not in the adult brain, whereas SHC3 expression is lower in the embryonic brain and increases post-natally. Pi-Y496 of TrkA can also be bound by FRS2. The competitive binding between Frs2 and SHC at this phospho-tyrosine residue contributes to a cellular switch between cell cycle progression (SHC recruitment) and cell cycle arrest/differentiation (Frs2 recruitment).
REACT_12019 (Reactome) Once Shc is phosphorylated, it dissociates from the receptor.
REACT_12023 (Reactome) Besides CRK, FRS2 also binds GRB2, the cyclin-dependent kinase substrate p13(SUC1), and the SH3 domain of SRC. There is also evidence for a C3G/CRK/SHP2/GAB2 complex, which is trafficked to the endosome, where C3G interacts with RAP1, triggering sustained RAP1 activation and prolonged B-RAF/MEK1/MAPK signalling. Crk-L is the predominant CRK isoform that interacts with C3G in several cell types; it is abundant in PC12 cells. PC12 cells also express high levels of Crk-II and low, but detectable, levels of Crk-I. Activation of Elk-1 by NGF was potently increased by cotransfection of exogenous Crk-II and Crk-L, but only weakly by Crk-I. In the absence of NGF, the expression of CRK isoforms activated Elk-1 minimally.
REACT_12030 (Reactome) The active form of RAL, RAL-GTP, activates SRC tyrosine kinase.
REACT_12032 (Reactome) p38 MAPK is known to activate the Ser/Thr protein kinase MAPKAP kinase 2 and a closely related kinase, MAPKAP kinase 3, through phosphorylation at multiple sites. According to some authors, NGF does not induce any significant activation of MAPKAPK2 activity in PC12 cells. Potential p38 signaling effectors include transcription factors, such as cAMP-response element-binding protein and MEF2, cytoskeleton modulators, and a number of protein kinases. After activation, MAPKAP kinase 2 and 3 move to the nucleus.
REACT_12036 (Reactome) TrkA can bind the Ras subfamly members RIT and RIN.
REACT_12037 (Reactome) Rap1 is a small G protein, necessary for prolonged ERK activity in PC12 cells. In such cells, NGF triggers a program of neuronal differentiation through the activation of a Rap1:B-RAF:ERK module Rap1 is activated by NGF, but not by epidermal growth factor (EGF), although both growth factors cause transient activation of RAS. Activation of Rap1 by NGF requires internalization of TRKA to intracellular vesicles, mostly endosomes, containing Rap1, B-RAF, MEK and ERKs. Rap1 does not co-localize with RAS. Therefore, the ability of Rap1 to bind RAF-1 without activating it might sequester RAF-1 from RAS. Activation of GEFs that couple to Rap1 as well as RAS might provide a mechanism to limit signals to RAS.
REACT_12041 (Reactome) The Ras-related protein, RAL becomes activated once GDP is replaced by GTP.
REACT_12046 (Reactome) Rap1 binds to B-RAF; as a consequence, B-RAF is recruited to endosomes. The binding event of Rap1 to B-RAF is thought to be very similar to the binding of RAS to RAF-1. In neuronal cells that express B-Raf, NGF induced activation of Rap1 promotes a sustained activation of ERKs and is required for the induction of electrical excitability and a subset of neuron-specific genes. As regards morphological differentiation (e. g. neurite outgrowth in PC12 cells), things are more complex. The transient activation of ERKs via RAS is not sufficient for neurite outgrowth in the absence of additional signals. On the contrary, constitutive activation of Rap1 is sufficient to trigger neurite outgrowth, but it is not necessary for this response.
Clearly, morphological differentiation of PC12 cells involves the activation of multiple pathways by NGF. Rap1 activates B-Raf, but inhibits RAF-1. Consequently, Rap1 could have two opposing functions: to limit ERK activation in B-RAF-negative cells and to increase ERK activation in B-Raf-positive cells.
REACT_12050 (Reactome) Rap1 binds to B-RAF; as a consequence, B-RAF is recruited to endosomes. The binding event of Rap1 to B-RAF is thought to be very similar to the binding of RAS to RAF-1. In neuronal cells that express B-Raf, NGF induced activation of Rap1 promotes a sustained activation of ERKs and is required for the induction of electrical excitability and a subset of neuron-specific genes. As regards morphological differentiation (e. g. neurite outgrowth in PC12 cells), things are more complex. The transient activation of ERKs via RAS is not sufficient for neurite outgrowth in the absence of additional signals. On the contrary, constitutive activation of Rap1 is sufficient to trigger neurite outgrowth, but it is not necessary for this response.
Clearly, morphological differentiation of PC12 cells involves the activation of multiple pathways by NGF. Rap1 activates B-Raf, but inhibits RAF-1. Consequently, Rap1 could have two opposing functions: to limit ERK activation in B-RAF-negative cells and to increase ERK activation in B-Raf-positive cells.
REACT_12055 (Reactome) On phosphorylation, ERK5 translocates to the nucleus.
REACT_12057 (Reactome) Activation of TRKA by NGF triggers STAT3 phosphorylation at Ser-727, and enhances the DNA binding and transcriptional activities of STAT3. Ser-727 phosphorylation of STAT3 begins within 5 min, and the levels of Ser(P) STAT3 remain elevated up to 30 min of NGF stimulation. Ser(P) STAT3 was localized to the cytoplasm, nuclei, and growth cones of neurites. Although the mechanisms by which STAT3 is activated by neurotrophins remaines unknown, phosphorylation of STAT3 at serine 727 might function as a convergent point for several signaling pathways triggered by Trk activation. Inhibition of STAT3 expression was found to attenuate NGF-induced transcription of immediate early genes, to suppress NGF-induced cyclin D1 expression, and to decrease BDNF-promoted neurite outgrowth in hippocampal neurons.
REACT_12061 (Reactome) Once phosphorylated, PLC-gamma dissociates from the receptor
REACT_12063 (Reactome) Activated TrkA induces the tyrosine phosphorylation of the lipid-anchored docking protein, FRS2. FRS2 is an adapter protein that links NGF receptors to downstream signaling pathways. It is involved in the activation of MAP kinases.
REACT_12066 (Reactome) Phosphorylation of ARMS by Trk receptor (on tyrosine 1096) enables ARMS to recruit Crk via it's SH2 domain and freeing the SH3 domain. The SH3 domain of Crk is then free to bind C3G for MAP kinase activation.
REACT_12071 (Reactome) RIT and RIN are activated by neurotrophins through unknown exchange factors. Activation reaches a maximal level between 5 and 15 min after NGF stimulation and remains elevated for at least 2 h. RIN, which is neuron-specific, might function as a component of a neuron specific B-RAF signalosome complex, in which RIN provides spatial and/or substrate specificity to the B-RAF-MEK kinase cascade to direct stimulation of p38 signaling.
REACT_12075 (Reactome) Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family. ERK5 is twice the size of the ERK1/2, containing a conserved amino terminal kinase domain that is 53% identical to ERK1/2, and a unique carboxyterminal region which contains potential binding sites for signalling molecules such as CRK, PI3 kinase and SRC. The second proline-rich region may interact with actin, targeting the kinase to a specific location in the cell. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in neurons, ERK5 appears to be activated only by neurotrophins. The small GTPase Rap1 and the MEKK2 or MEKK3 kinases are critical upstream signaling molecules mediating neurotrophin stimulation of ERK5 in neurons. MEKK2 or MEKK3 activate MEK5, which appears to be localised in intracellular vesicles. MEK5 then activates ERK5. Once phosphorylated, ERK5 translocates to the nucleus.
REACT_12083 (Reactome) Rap1 is a small G protein, necessary for prolonged ERK activity in PC12 cells. In such cells, NGF triggers a program of neuronal differentiation through the activation of a Rap1:B-RAF:ERK module Rap1 is activated by NGF, but not by epidermal growth factor (EGF), although both growth factors cause transient activation of RAS. Activation of Rap1 by NGF requires internalization of TRKA to intracellular vesicles, mostly endosomes, containing Rap1, B-RAF, MEK and ERKs. Rap1 does not co-localize with RAS. Therefore, the ability of Rap1 to bind RAF-1 without activating it might sequester RAF-1 from RAS. Activation of GEFs that couple to Rap1 as well as RAS might provide a mechanism to limit signals to RAS.
REACT_12384 (Reactome) The PI3K regulatory subunit p85 binds to IRS1 or IRS2, tyrosine-phosphorylated at YXXM motifs, through its SH2 domain.
As the p85 subunt is constitutively associated with the p110 catalytic subunit, the outcome is that the whole PI3K complex is recruited to the membrane. The interaction at the plasma membrane of the p85 regulatory subunit with the p110 catalytic subunit of PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) causes a conformational change, resulting in activation of the catalytic subunit.
REACT_12385 (Reactome) Of the internalized NGF:TRK complexes, many undergo recycling and/or proteolysis. Only a small fraction is retrogradely transported. Vesicles containing neurotrophin, activated receptors and downstream kinases are transported through axons by the action of dynein, which produces a force towards the end of microtubules.
REACT_12397 (Reactome) Dynamin is a microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. It is involved in vesicle trafficking processes and is necessary for endocytosis.

Dynamins are large GTPases that bind to PIP2-containing membranes, several SH3-domain containing proteins and cytoskeletal modifiers. They self-polymerize in a GTP dependent manner, catalyzing the scission of invaginating membranes during endocytosis (Praefcke & McMahon, 2004).

There are three dynamins in humans: dynamin I is neuron-specific; dynamin II shows ubiquitous expression; dynamin III is expressed in testis, brain, lung and blood platelets.
REACT_12406 (Reactome) Following translocation to the nucleus, ERK1/2 directly phosphorylates key effectors, including the ubiquitous transcription factors ELK1 (Ets like protein 1). At least five residues in the C terminal domain of ELK1 are phosphorylated upon growth factor stimulation. ELK1 can form a ternary complex with the serum response factor (SRF) and consensus sequences, such as serum response elements (SRE), on DNA, thus stimulating transcription of a set of immediate early genes like c fos.
REACT_12413 (Reactome) The MEF2 (Myocyte-specific enhancer factor 2) proteins constitute a family of transcription factors: MEF2A, MEF2B, MEF2C, and MEF2D. MEF2A and MEF2C are known substrates of ERK5, and their transactivating activity can be stimulated by ERK5 via direct phosphorylation. MEF2A and MEF2C are expressed in developing and adult brain including cortex and cerebellum.
REACT_12434 (Reactome) IRS1 and IRS2 are tyrosine phosphorylated at multiple YXXM motifs by the active TRKA kinase.
REACT_12437 (Reactome) Cyclic-AMP-dependent transcription factor 1 (ATF1) can be phosphorylated at Serine 63 by MSK1, thus activating it.
REACT_12439 (Reactome) Over 10 dual specificity phosphatases (DUSPs) active an MAP kinases are known. Among them, some possess good ERK docking sites and so are more specific for the ERKS (DUSP 3, 4, 6, 7), others are more specific for p38MAPK (DUSP1 and 10), while others do not seem to discriminate. It is noteworthy that transcription of DUSP genes is induced by growth factor signaling itself, so that these phosphatases provide feedback attenuation of signaling. Moreover, differential activation of DUSPs by different stimuli is thought to contribute to pathway specificity.
REACT_12487 (Reactome) The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.
RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.
Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2.

REACT_12502 (Reactome) IRS1 and IRS2 bind directly to TRK receptors phosphorylated at Y490, through their phosphotyrosine- binding (PTB) domains.
REACT_12539 (Reactome) ERKs are inactivated by the protein phosphatase 2A (PP2A). The PP2A holoenzyme is a heterotrimer that consists of a core dimer, composed of a scaffold (A) and a catalytic (C) subunit that associates with a variety of regulatory (B) subunits. The B subunits have been divided into gene families named B (or PR55), B0 (or B56 or PR61) and B00 (or PR72). Each family comprises several members. B56 family members of PP2A in particular, increase ERK dephosphorylation, without affecting its activation by MEK.
Induction of PP2A is involved in the extracellular signal-regulated kinase (ERK) signalling pathway, in which it provides a feedback control, as well as in a broad range of other cellular processes, including transcriptional regulation and control of the cell cycle.This diversity of functions is conferred by a diversity of regulatory subunits, the combination of which can give rise to over 50 different forms of PP2A. For example, five distinct mammalian genes encode members of the B56 family, called B56a, b, g, d and e, generating at least eight isoforms. Whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown.
REACT_12546 (Reactome) MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by p38MAPK through phosphorylation at four key residues.

REACT_12559 (Reactome) Both BDNF and NGF treatment recruits clathrin and AP2 (adaptor protein 2) proteins to the plasma membrane. Clathrin is the major protein of the polyhedral coat of vesicles. The AP2 complex mediates both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules.
REACT_12576 (Reactome) MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues.
REACT_12577 (Reactome) Several guanine exchange factors (GEFs) for the Rho family of GTPases contain PH domains that bind to PIP3. RhoA protein activation is a mechanism whereby PI3K acts independently of AKT.
REACT_12586 (Reactome) p38 MAPK activation leads to CREB Serine 133 phosphorylation through the activation of MAPKAP kinase 2 or the closely related MAPKAP kinase 3.
REACT_12622 (Reactome) CREB is phosphorylated at Serine 133 by RSK1/2/3.
REACT_12624 (Reactome) PI3-kinase phosphorylates several phosphatidyl-inositides (phospholipids) at the plasma membrane: the most relevant is PtdIns(3,4,5)P3, also named PIP3.
REACT_12631 (Reactome) MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).
REACT_176 (Reactome) Tyrosine receptor kinase stimulation phosphorylates Shc which recruits the SH2 domain of the adaptor protein GRB2, which is complexed with SOS, an exchange factor for p21ras and RAC, through its SH3 domain. Besides SOS, the GRB2 SH3 domain can associate with other intracellular targets, including GAB1. Erk and Rsk mediated phosphorylation results in dissociation of the SOS-GRB2 complex. This may explain why Erk activation through Shc and SOS-GRB2 is transient. Inactive p21ras-GDP is found anchored to the plasma membrane by a farnesyl residue. As Shc is phosphorylated by the the stimulated receptor near to the plasma membrane, the SOS-GRB2:Shc interaction brings the SOS enzyme into close proximity to p21ras.
REACT_2010 (Reactome) SOS promotes the formation of GTP-bound RAS, thus activating this protein. RAS activation results in activation of the protein kinases RAF1, B-Raf, and MAP-ERK kinase kinase (MEKK), and the catalytic subunit of PI3K, as well as of a series of RALGEFs. The activation cycle of RAS GTPases is regulated by their interaction with specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs promote activation by inducing the release of GDP, whereas GAPs inactivate RAS-like proteins by stimulating their intrinsic GTPase activity. NGF-induced RAS activation via SHC-GRB2-SOS is maximal at 2 min but it is no longer detected after 5 min. Therefore, the transient activation of RAS obtained through SHC-GRB2-SOS is insufficient for the prolonged activation of ERKs found in NGF-treated cells.

REACT_9962 (Reactome) NGF binding induces a conformational change in TRKA, which entails the activation of the receptor kinase domain. TRK receptor activation results in phosphorylation of several of ten evolutionary conserved tyrosines present in the cytoplasmic domain of each receptor. Phosphorylation of the three tyrosines in the activation loop of the kinase domain (Y670, Y674, and Y675 in TRKA) enhances tyrosine kinase activity. Phosphorylation of TRKA Y490 and Y785 creates docking sites for proteins containing SH2 or PTB domains: Y490 is the docking site for SHC, FRS2 and IRS1/2, Y785 interacts with PLC-gamma-1. Three other tyrosine residues are important for signalling but it is not clear how. It is possible that they play a structural role in the receptor. Therefore, full activity of TRKA receptor requires eight tyrosine residues.
Human TRKA comes in two isoforms, named TRKA- I (790 a.a long) and TRKA- II (796 a.a. long). The tyrosine phosphorylation site numbering refers to TRKA- I. The site numbering in TRK-II is equal to TRK- I numbering + 6 (that is: Y490 in TRK- I corresponds to Y496 in TRK- II, and so on).The same modifications occur at the homologous sites of rat TrkA, which also comes in the two isoforms I and II.

REACT_9980 (Reactome) Adenosine, acting through A2A receptors can induce TrkA activation. The mechanism of this activation is not understood.
RHOAREACT_12577 (Reactome)
RIT/RIN-GDPREACT_12036 (Reactome)
RPS6KA5REACT_12546 (Reactome)
RPS6KA5REACT_12576 (Reactome)
Rap1-GDPREACT_12037 (Reactome)
Rap1-GDPREACT_12083 (Reactome)
Rap1-GTPArrowREACT_12037 (Reactome)
Rap1-GTPArrowREACT_12083 (Reactome)
Rap1-GTPREACT_12050 (Reactome)
Rap1-GTPmim-catalysisREACT_12050 (Reactome)
Ras-GTP RalGDS complexmim-catalysisREACT_12041 (Reactome)
Ribosomal protein S6 kinaseREACT_12487 (Reactome)
SH3GL2REACT_12397 (Reactome)
SHCREACT_12017 (Reactome)
SRC-1REACT_12030 (Reactome)
STAT3REACT_12057 (Reactome)
YWHABArrowREACT_12046 (Reactome)
beta-NGF dimer TrkA receptor dimerREACT_9962 (Reactome)
beta-NGF dimer TrkA receptor dimermim-catalysisREACT_9962 (Reactome)
beta-NGF dimer TrkA receptorREACT_10014 (Reactome)
mature beta-NGF homodimerREACT_10088 (Reactome)
p-4S,T336-ELK1ArrowREACT_12406 (Reactome)
p-4Y-PLCG1ArrowREACT_12061 (Reactome)
p-ERK1/2/5REACT_12439 (Reactome)
p-ERK1/2/5REACT_12539 (Reactome)
p-ERK1/2/5mim-catalysisREACT_12487 (Reactome)
p-MAPK p38 alpha/betamim-catalysisREACT_12546 (Reactome)
p-S133-CREB1ArrowREACT_12586 (Reactome)
p-S133-CREB1ArrowREACT_12622 (Reactome)
p-S133-CREB1ArrowREACT_12631 (Reactome)
p-S212,S360,S376,T581-RPS6KA5ArrowREACT_12546 (Reactome)
p-S212,S360,S376,T581-RPS6KA5ArrowREACT_12576 (Reactome)
p-S212,S360,S376,T581-RPS6KA5mim-catalysisREACT_12437 (Reactome)
p-S212,S360,S376,T581-RPS6KA5mim-catalysisREACT_12631 (Reactome)
p-S63-ATF1ArrowREACT_12437 (Reactome)
p-S727-STAT3ArrowREACT_12057 (Reactome)
p-SHCArrowREACT_12019 (Reactome)
p-SHCREACT_176 (Reactome)
p-T218,Y220-MAPK7ArrowREACT_12075 (Reactome)
p-T218,Y220-MAPK7mim-catalysisREACT_12413 (Reactome)
p-T222,S272-MAPKAPK2mim-catalysisREACT_12586 (Reactome)
p-Y419-SRC-1ArrowREACT_12030 (Reactome)
p-Y419-SRC-1mim-catalysisREACT_12016 (Reactome)
p21 RAS GDPREACT_2010 (Reactome)
p21 RAS GTPArrowREACT_2010 (Reactome)
p21 RAS GTPREACT_12001 (Reactome)
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