Gastrin-CREB signaling via PKC and MAPK (Homo sapiens)

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6, 31, 50129245, 14128, 4948, 52392, 4615, 433716, 273203513264717, 19, 24, 41, 4225cytosolnucleoplasmNMUR2 GNA14 GAST(76-92)AGT(34-41) GPCRs that activateGq/11RAF/MAP kinasecascadeL-Glu PAF MCHR1 G-protein beta-gammacomplexGDP TRH(84-86) TXA2 GDPAVPR1B GAST(76-92) XCR1 HRH1 GHSR PROK1 NRAS QRFP EDN2 CCKBR ATP XCL2 thrombin heavy chainGNAQ CYSLTR2 PTAFR AcCho CCK PRKCA TRH(135-137) LXA4 NPSR1 NMUR1 TRH(152-154) KRAS TRH(227-229) GNA14 TRH(186-188) p21 RAS:GDPGNRHR ADRBK1DAG ADR ATP BDKRB1 MCHR2 FFAR2 TRIO LPAR1 TRH(186-188) OLEA TAC1(98-107) O-octanoyl-L-serine-GHRL-1(24-50) DDCX TACR2 EDN3 ATPthrombin light chainNTSR2 NMU AGTR1 KISS1R O-octanoyl-L-serine-GHRL-1(24-51) Valerate HCOOH NPS(1-467) MT-RNR2 NTSR1 GPR17 LPAR2 G-protein alpha(q/11):GDPGNA14 GPR68 EDN2 LTC4 DecS-GHRL-1(24-51) OXT(20-28) KRAS HBEGF(63-148)FFAR3 LTB4R AVP(20-28) NMS GDP RGZ CCKAR P2RY10 HTR2A PGE2 GNA14 UDP HCRT(34-66) OPN4 GDP CHRM5 5HT NPS(1-467) UTS2 AGT(34-41) CH3COO- GNA14 NMB(47-56) NAd GNAQ HCRT(34-66) GNAQ DecS-GHRL-1(24-50) PLC beta:G alpha(q/11)ADRA1A CH3COO- HTR2C LTE4 GAST(76-92) GNA11 GNA15 CYSLTR1 CYSLTR2 KISS1(68-121) MCHR2 HBEGF(20-62)GNA14 GNRHR GDPPentadecanoic acid F2RL2(22-374) PROKR2 GNA15 UTS2B GNA14 F2R(27-425) Ligand:GPCRcomplexesthatactivateGq/11:Heterotrimeric G-protein Gq (inactive)HCRTR2 Valerate PMCH(147-165) NPFFR1 GNA15 5HT KISS1R RGZ EDN1 LPAR3 XCR1 GRP(24-50) TACR1 UTS2B LTD4 XCL2 PAF P2RY1 PMCH(147-165) TRIO family RhoGEFsTBXA2R CREB1TRH(114-116) F2RL1(37-397) TAC3 FFAR1 LPAR4 NTSR2 LPAR4 GNA11 TXA2 DecS-GHRL-1(24-50) GNA11 L-Lys O-octanoyl-L-serine-GHRL-1(24-50) KISS1(68-121) PROKR1 PROK2 AVP(20-28) GNRHR2 GNA11 TAC3 GRB2-1 BDKRB2 GTP GNA15 L-Arg MLN(26-47) PLCB4 GTP LTB4R LTE4 F2RL2(22-374) GTP PLC-betaCHRM1 GRK5GNAQ HRAS PALM TACR3 GNAQ GRM5 GNA11 LPA GRP(24-50) GTP EDNRB Ligand:GPCRcomplexesthatactivateGq/11:Heterotrimeric G-protein Gq (active)HCRT(70-97) CHRM3 DecS-GHRL-1(24-51) LTB4R2 GDP LPAR1 APP(672-713) GPRC6A GNA11 HCRTR1 QRFP AVPR1A HRH1 G-protein alpha(q/11): GTPGlucagon ADPBDKRB1 HTR2A GPRC6A TACR3 LPAR6 AVPR1B HCRT(70-97) HBEGF(149-208)PTGER1 GTP NPFFR1 G-protein alpha(q):GRK2OXTR PTGFR H+ NPFFR2 ADRA1D ADP ANXA1 GNRHR2 MT-RNR2 NTS(151-163) FFAR2 NMU F2RL3(18-385) ADRA1A F2R(27-425) LXA4 UTS2R LTB4 I(1,4,5)P3CHRM3 OXT(20-28) AcCho MLNR EDN1 MLNR PROK2 PROKR2 Ca2+ PI(4,5)P2CYSLTR1 GRB2-1 CHRM5 Effects of PIP2hydrolysisQRFPR P2RY2 p-ERK1/2/5Ca2+ BDKRB2 SOS1 EDNRB p-6Y-EGFR FPR2 H+ LTB4R2 DAGADRBK1 TAC1(58-68) GNA14 GRK5 MCHR1 GCGR NMB(47-56) CCKBRGRB2:SOS1:HB-EGF:p-6Y-EGFREDN3 PTGFR Glucagon NMS PI3K alphaCCKBR TRH(152-154) BUT p-6Y-EGFR APP(672-713) HRAS Pentadecanoic acid ANXA1 NPFFR2 NRAS PRKCALTD4 XCL1 GNA14 MMP3GNRH1(24-33) TACR2 EtCOO- or C2H5COO- GNAQ HCOOH CCKBR GNA11 GNAQ PLCB2 UTS2R P2RY10 LTB4 UDP L-Orn P2RY11 NPSR1 EDNRA XCL1 GTP PLCB1 OPN4 HCRTR2 GTPGNRH2(24-33) ARHGEF25 PROKR1 EtCOO- or C2H5COO- thrombin light chainPROK1 GHSR GNRH2(24-33) GAST(76-92) Gastrin:CCKBRGPR68 TAC1(98-107) LPAR5 NTS(151-163) Ribosomal protein S6kinaseBUT GNA15 PLCB3 TRH(84-86) P2RY6 GNAQ HBEGF(63-148) GPR65 CASR Bradykinin KALRN P2RY6 TRHR G-protein alpha(q/11)PTGER1 SOS1 CASR SAA1(19-122) DDCX GPR132 ADR GNA15 GPR65 PTAFR LPAR6 G-protein alpha(q/11):Trio familyRhoGEFsGNA15 NPFF(69-76) GRM5 CCK TRH(227-229) PIK3CA GNA15 LPA ADP GPR132 GPR4 GNAQ TACR1 LPAR5 NAd FFAR3 GTP TRH(135-137) FPR2 GNRH1(24-33) L-Glu TRHR Protein Kinase C,alpha type: DAGFFAR1 G-protein alpha(q):GRK5Hist GPR17 L-Orn thrombin heavy chainHTR2B ADPHeterotrimericG-protein Gq/11(inactive)p-S133-CREB1F2RL1(37-397) GNAQ Ligand:GPCRcomplexes thatactivate Gq/11GRM1 LTC4 ATPNMUR2 P2RY1 GTPUTS2 F2RL3(18-385) p21 RAS:GTPADRA1B EDNRA PGF2a HCRTR1 G-protein alpha(q/11):PI3K alphaCHRM1 QRFPR GRB2-1:SOS1NTSR1 OXTR HBEGF(63-148) P2RY2 GNA11 HXA AGTR1 CCL23-2 PGE2 LPAR2 SAA1(19-122) HB-EGF:p-6Y-EGFRdimerHXA PIK3CA Bradykinin PGF2a HTR2B NMUR1 AVPR1A Hist LPAR3 PALM TRH(114-116) GNA11 TBXA2R Ligands of GPCRsthat activate Gq/11OLEA GCGR L-Lys GNA11 ADRA1B GRM1 EGFRNPFF(69-76) MLN(26-47) GNA15 P2RY11 GNA15 L-Arg CCL23-2 CCKAR GTP RGS proteins activefor G alpha (q)HBEGF(20-208)O-octanoyl-L-serine-GHRL-1(24-51) Phospho-Ribosomalprotein S6 kinaseHTR2C GPR4 ADRA1D GNA14 TAC1(58-68) 10, 117, 8, 22, 23, 29...21, 3621, 3621, 3621, 364, 18, 34


Description

Gastrin is a hormone whose main function is to stimulate secretion of hydrochloric acid by the gastric mucosa, which results in gastrin formation inhibition. This hormone also acts as a mitogenic factor for gastrointestinal epithelial cells. Gastrin has two biologically active peptide forms, G34 and G17.Gastrin gene expression is upregulated in both a number of pre-malignant conditions and in established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical gastrin cholecystokinin B receptor CCK-BR, its isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion (Wank 1995, de Weerth et al. 1999, Grabowska & Watson 2007) Source:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
129720view01:33, 22 May 2024EweitzModified title
116412view09:06, 7 May 2021EweitzModified title
115053view16:59, 25 January 2021ReactomeTeamReactome version 75
113497view11:57, 2 November 2020ReactomeTeamReactome version 74
112697view16:09, 9 October 2020ReactomeTeamReactome version 73
101614view11:48, 1 November 2018ReactomeTeamreactome version 66
101150view21:34, 31 October 2018ReactomeTeamreactome version 65
100678view20:07, 31 October 2018ReactomeTeamreactome version 64
100228view16:52, 31 October 2018ReactomeTeamreactome version 63
99779view15:18, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99335view12:47, 31 October 2018ReactomeTeamreactome version 62
93801view13:37, 16 August 2017ReactomeTeamreactome version 61
93339view11:20, 9 August 2017ReactomeTeamreactome version 61
87453view14:00, 22 July 2016MkutmonOntology Term : 'signaling pathway' added !
86425view09:17, 11 July 2016ReactomeTeamreactome version 56
83266view10:35, 18 November 2015ReactomeTeamVersion54
81375view12:54, 21 August 2015ReactomeTeamVersion53
76844view08:07, 17 July 2014ReactomeTeamFixed remaining interactions
76548view11:53, 16 July 2014ReactomeTeamFixed remaining interactions
75881view09:53, 11 June 2014ReactomeTeamRe-fixing comment source
75581view10:41, 10 June 2014ReactomeTeamReactome 48 Update
74936view13:46, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74580view08:37, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
5HT MetaboliteCHEBI:28790 (ChEBI)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ADR MetaboliteCHEBI:28918 (ChEBI)
ADRA1A ProteinP35348 (Uniprot-TrEMBL)
ADRA1B ProteinP35368 (Uniprot-TrEMBL)
ADRA1D ProteinP25100 (Uniprot-TrEMBL)
ADRBK1 ProteinP25098 (Uniprot-TrEMBL)
ADRBK1ProteinP25098 (Uniprot-TrEMBL)
AGT(34-41) ProteinP01019 (Uniprot-TrEMBL)
AGTR1 ProteinP30556 (Uniprot-TrEMBL)
ANXA1 ProteinP04083 (Uniprot-TrEMBL)
APP(672-713) ProteinP05067 (Uniprot-TrEMBL)
ARHGEF25 ProteinQ86VW2 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AVP(20-28) ProteinP01185 (Uniprot-TrEMBL)
AVPR1A ProteinP37288 (Uniprot-TrEMBL)
AVPR1B ProteinP47901 (Uniprot-TrEMBL)
AcCho MetaboliteCHEBI:15355 (ChEBI)
BDKRB1 ProteinP46663 (Uniprot-TrEMBL)
BDKRB2 ProteinP30411 (Uniprot-TrEMBL)
BUT MetaboliteCHEBI:30772 (ChEBI)
Bradykinin ProteinP01042 (Uniprot-TrEMBL)
CASR ProteinP41180 (Uniprot-TrEMBL)
CCK ProteinP06307 (Uniprot-TrEMBL)
CCKAR ProteinP32238 (Uniprot-TrEMBL)
CCKBR ProteinP32239 (Uniprot-TrEMBL)
CCKBRProteinP32239 (Uniprot-TrEMBL)
CCL23-2 ProteinP55773-2 (Uniprot-TrEMBL)
CH3COO- MetaboliteCHEBI:15366 (ChEBI)
CHRM1 ProteinP11229 (Uniprot-TrEMBL)
CHRM3 ProteinP20309 (Uniprot-TrEMBL)
CHRM5 ProteinP08912 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
CYSLTR1 ProteinQ9Y271 (Uniprot-TrEMBL)
CYSLTR2 ProteinQ9NS75 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAGMetaboliteCHEBI:17815 (ChEBI)
DDCX MetaboliteCHEBI:30805 (ChEBI)
DecS-GHRL-1(24-50) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
DecS-GHRL-1(24-51) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
EDN1 ProteinP05305 (Uniprot-TrEMBL)
EDN2 ProteinP20800 (Uniprot-TrEMBL)
EDN3 ProteinP14138 (Uniprot-TrEMBL)
EDNRA ProteinP25101 (Uniprot-TrEMBL)
EDNRB ProteinP24530 (Uniprot-TrEMBL)
EGFRProteinP00533 (Uniprot-TrEMBL)
Effects of PIP2 hydrolysisPathwayR-HSA-114508 (Reactome) Hydrolysis of phosphatidyl inositol-bisphosphate (PIP2) by phospholipase C (PLC) produces diacylglycerol (DAG) and inositol triphosphate (IP3). Both are potent second messengers. IP3 diffuses into the cytosol, but as DAG is a hydrophobic lipid it remains within the plasma membrane. IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, while DAG activates the conventional and unconventional protein kinase C (PKC) isoforms, facilitating the translocation of PKC from the cytosol to the plasma membrane. The effects of DAG are mimicked by tumor-promoting phorbol esters. DAG is also a precursor for the biosynthesis of prostaglandins, the endocannabinoid 2-arachidonoylglycerol and an activator of a subfamily of TRP-C (Transient Receptor Potential Canonical) cation channels 3, 6, and 7.
EtCOO- or C2H5COO- MetaboliteCHEBI:30768 (ChEBI)
F2R(27-425) ProteinP25116 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
F2RL1(37-397) ProteinP55085 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
F2RL2(22-374) ProteinO00254 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
F2RL3(18-385) ProteinQ96RI0 (Uniprot-TrEMBL) This is the inactive form of the receptor, before protease activation. Proteinase (protease) activated receptors are activated by the cleavage of an N-terminal extracellular segment by serine proteases, particularly thrombin which activates PAR1, 3 and 4. The cleaved fragment is an activating ligand for the receptor; synthetic peptide mimics of the N-terminal fragment can activate uncleaved receptors.
FFAR1 ProteinO14842 (Uniprot-TrEMBL)
FFAR2 ProteinO15552 (Uniprot-TrEMBL)
FFAR3 ProteinO14843 (Uniprot-TrEMBL)
FPR2 ProteinP25090 (Uniprot-TrEMBL)
G-protein alpha (q):GRK2ComplexR-HSA-416515 (Reactome)
G-protein alpha (q):GRK5ComplexR-HSA-416517 (Reactome)
G-protein alpha (q/11): GTPComplexR-HSA-114534 (Reactome)
G-protein alpha (q/11):GDPComplexR-HSA-114556 (Reactome)
G-protein alpha (q/11):PI3K alphaComplexR-HSA-416356 (Reactome)
G-protein alpha

(q/11):Trio family

RhoGEFs		ComplexR-HSA-400608 (Reactome)
G-protein alpha (q/11)R-HSA-374848 (Reactome)
G-protein beta-gamma complexComplexR-HSA-167434 (Reactome)
GAST(76-92) ProteinP01350 (Uniprot-TrEMBL)
GAST(76-92)ProteinP01350 (Uniprot-TrEMBL)
GCGR ProteinP47871 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GHSR ProteinQ92847 (Uniprot-TrEMBL)
GNA11 ProteinP29992 (Uniprot-TrEMBL)
GNA14 ProteinO95837 (Uniprot-TrEMBL)
GNA15 ProteinP30679 (Uniprot-TrEMBL)
GNAQ ProteinP50148 (Uniprot-TrEMBL)
GNRH1(24-33) ProteinP01148 (Uniprot-TrEMBL)
GNRH2(24-33) ProteinO43555 (Uniprot-TrEMBL)
GNRHR ProteinP30968 (Uniprot-TrEMBL)
GNRHR2 ProteinQ96P88 (Uniprot-TrEMBL)
GPCRs that activate Gq/11R-HSA-791493 (Reactome)
GPR132 ProteinQ9UNW8 (Uniprot-TrEMBL)
GPR17 ProteinQ13304 (Uniprot-TrEMBL)
GPR4 ProteinP46093 (Uniprot-TrEMBL)
GPR65 ProteinQ8IYL9 (Uniprot-TrEMBL)
GPR68 ProteinQ15743 (Uniprot-TrEMBL)
GPRC6A ProteinQ5T6X5 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2:SOS1:HB-EGF:p-6Y-EGFRComplexR-HSA-2179409 (Reactome)
GRK5 ProteinP34947 (Uniprot-TrEMBL)
GRK5ProteinP34947 (Uniprot-TrEMBL)
GRM1 ProteinQ13255 (Uniprot-TrEMBL)
GRM5 ProteinP41594 (Uniprot-TrEMBL)
GRP(24-50) ProteinP07492 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Gastrin:CCKBRComplexR-HSA-870262 (Reactome)
Glucagon ProteinP01275 (Uniprot-TrEMBL)
H+ MetaboliteCHEBI:15378 (ChEBI)
HB-EGF:p-6Y-EGFR dimerComplexR-HSA-2179410 (Reactome)
HBEGF(149-208)ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(20-208)ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(20-62)ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(63-148) ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(63-148)ProteinQ99075 (Uniprot-TrEMBL)
HCOOH MetaboliteCHEBI:30751 (ChEBI)
HCRT(34-66) ProteinO43612 (Uniprot-TrEMBL)
HCRT(70-97) ProteinO43612 (Uniprot-TrEMBL)
HCRTR1 ProteinO43613 (Uniprot-TrEMBL)
HCRTR2 ProteinO43614 (Uniprot-TrEMBL)
HRAS ProteinP01112 (Uniprot-TrEMBL)
HRH1 ProteinP35367 (Uniprot-TrEMBL)
HTR2A ProteinP28223 (Uniprot-TrEMBL)
HTR2B ProteinP41595 (Uniprot-TrEMBL)
HTR2C ProteinP28335 (Uniprot-TrEMBL)
HXA MetaboliteCHEBI:17120 (ChEBI)
Heterotrimeric

G-protein Gq/11

(inactive)		ComplexR-HSA-114557 (Reactome)
Hist MetaboliteCHEBI:18295 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
KALRN ProteinO60229 (Uniprot-TrEMBL)
KISS1(68-121) ProteinQ15726 (Uniprot-TrEMBL)
KISS1R ProteinQ969F8 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
L-Arg MetaboliteCHEBI:16467 (ChEBI)
L-Glu MetaboliteCHEBI:16015 (ChEBI)
L-Lys MetaboliteCHEBI:18019 (ChEBI)
L-Orn MetaboliteCHEBI:15729 (ChEBI)
LPA MetaboliteCHEBI:52288 (ChEBI)
LPAR1 ProteinQ92633 (Uniprot-TrEMBL)
LPAR2 ProteinQ9HBW0 (Uniprot-TrEMBL)
LPAR3 ProteinQ9UBY5 (Uniprot-TrEMBL)
LPAR4 ProteinQ99677 (Uniprot-TrEMBL)
LPAR5 ProteinQ9H1C0 (Uniprot-TrEMBL)
LPAR6 ProteinP43657 (Uniprot-TrEMBL)
LTB4 MetaboliteCHEBI:15647 (ChEBI)
LTB4R ProteinQ15722 (Uniprot-TrEMBL)
LTB4R2 ProteinQ9NPC1 (Uniprot-TrEMBL)
LTC4 MetaboliteCHEBI:16978 (ChEBI)
LTD4 MetaboliteCHEBI:28666 (ChEBI)
LTE4 MetaboliteCHEBI:15650 (ChEBI)
LXA4 MetaboliteCHEBI:6498 (ChEBI)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (active)		ComplexR-HSA-749447 (Reactome)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (inactive)		ComplexR-HSA-749451 (Reactome)
Ligand:GPCR

complexes that

activate Gq/11		R-HSA-380110 (Reactome)
Ligands of GPCRs that activate Gq/11R-HSA-791492 (Reactome)
MCHR1 ProteinQ99705 (Uniprot-TrEMBL)
MCHR2 ProteinQ969V1 (Uniprot-TrEMBL)
MLN(26-47) ProteinP12872 (Uniprot-TrEMBL)
MLNR ProteinO43193 (Uniprot-TrEMBL)
MMP3ProteinP08254 (Uniprot-TrEMBL)
MT-RNR2 ProteinQ8IVG9 (Uniprot-TrEMBL)
NAd MetaboliteCHEBI:18357 (ChEBI)
NMB(47-56) ProteinP08949 (Uniprot-TrEMBL)
NMS ProteinQ5H8A3 (Uniprot-TrEMBL)
NMU ProteinP48645 (Uniprot-TrEMBL)
NMUR1 ProteinQ9HB89 (Uniprot-TrEMBL)
NMUR2 ProteinQ9GZQ4 (Uniprot-TrEMBL)
NPFF(69-76) ProteinO15130 (Uniprot-TrEMBL)
NPFFR1 ProteinQ9GZQ6 (Uniprot-TrEMBL)
NPFFR2 ProteinQ9Y5X5 (Uniprot-TrEMBL)
NPS(1-467) ProteinP0C0P6 (Uniprot-TrEMBL)
NPSR1 ProteinQ6W5P4 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NTS(151-163) ProteinP30990 (Uniprot-TrEMBL)
NTSR1 ProteinP30989 (Uniprot-TrEMBL)
NTSR2 ProteinO95665 (Uniprot-TrEMBL)
O-octanoyl-L-serine-GHRL-1(24-50) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
O-octanoyl-L-serine-GHRL-1(24-51) ProteinQ9UBU3-1 (Uniprot-TrEMBL)
OLEA MetaboliteCHEBI:16196 (ChEBI)
OPN4 ProteinQ9UHM6 (Uniprot-TrEMBL)
OXT(20-28) ProteinP01178 (Uniprot-TrEMBL)
OXTR ProteinP30559 (Uniprot-TrEMBL)
P2RY1 ProteinP47900 (Uniprot-TrEMBL)
P2RY10 ProteinO00398 (Uniprot-TrEMBL)
P2RY11 ProteinQ96G91 (Uniprot-TrEMBL)
P2RY2 ProteinP41231 (Uniprot-TrEMBL)
P2RY6 ProteinQ15077 (Uniprot-TrEMBL)
PAF MetaboliteCHEBI:52450 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PGE2 MetaboliteCHEBI:15551 (ChEBI)
PGF2a MetaboliteCHEBI:15553 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alphaComplexR-HSA-198379 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PLC beta:G alpha (q/11)ComplexR-HSA-398158 (Reactome)
PLC-betaR-HSA-111854 (Reactome)
PLCB1 ProteinQ9NQ66 (Uniprot-TrEMBL)
PLCB2 ProteinQ00722 (Uniprot-TrEMBL)
PLCB3 ProteinQ01970 (Uniprot-TrEMBL)
PLCB4 ProteinQ15147 (Uniprot-TrEMBL)
PMCH(147-165) ProteinP20382 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCAProteinP17252 (Uniprot-TrEMBL)
PROK1 ProteinP58294 (Uniprot-TrEMBL)
PROK2 ProteinQ9HC23 (Uniprot-TrEMBL)
PROKR1 ProteinQ8TCW9 (Uniprot-TrEMBL)
PROKR2 ProteinQ8NFJ6 (Uniprot-TrEMBL)
PTAFR ProteinP25105 (Uniprot-TrEMBL)
PTGER1 ProteinP34995 (Uniprot-TrEMBL)
PTGFR ProteinP43088 (Uniprot-TrEMBL)
Pentadecanoic acid MetaboliteCHEBI:42504 (ChEBI)
Phospho-Ribosomal protein S6 kinaseR-HSA-199849 (Reactome)
Protein Kinase C, alpha type: DAGComplexR-HSA-422275 (Reactome)
QRFP ProteinP83859 (Uniprot-TrEMBL)
QRFPR ProteinQ96P65 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RGS proteins active for G alpha (q)R-HSA-921123 (Reactome)
RGZ MetaboliteCHEBI:50122 (ChEBI)
Ribosomal protein S6 kinaseR-HSA-199858 (Reactome)
SAA1(19-122) ProteinP0DJI8 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
TAC1(58-68) ProteinP20366 (Uniprot-TrEMBL)
TAC1(98-107) ProteinP20366 (Uniprot-TrEMBL)
TAC3 ProteinQ9UHF0 (Uniprot-TrEMBL)
TACR1 ProteinP25103 (Uniprot-TrEMBL)
TACR2 ProteinP21452 (Uniprot-TrEMBL)
TACR3 ProteinP29371 (Uniprot-TrEMBL)
TBXA2R ProteinP21731 (Uniprot-TrEMBL)
TRH(114-116) ProteinP20396 (Uniprot-TrEMBL)
TRH(135-137) ProteinP20396 (Uniprot-TrEMBL)
TRH(152-154) ProteinP20396 (Uniprot-TrEMBL)
TRH(186-188) ProteinP20396 (Uniprot-TrEMBL)
TRH(227-229) ProteinP20396 (Uniprot-TrEMBL)
TRH(84-86) ProteinP20396 (Uniprot-TrEMBL)
TRHR ProteinP34981 (Uniprot-TrEMBL)
TRIO ProteinO75962 (Uniprot-TrEMBL)
TRIO family RhoGEFsR-HSA-399963 (Reactome)
TXA2 MetaboliteCHEBI:15627 (ChEBI)
UDP MetaboliteCHEBI:17659 (ChEBI)
UTS2 ProteinO95399 (Uniprot-TrEMBL)
UTS2B ProteinQ765I0 (Uniprot-TrEMBL)
UTS2R ProteinQ9UKP6 (Uniprot-TrEMBL)
Valerate MetaboliteCHEBI:31011 (ChEBI)
XCL1 ProteinP47992 (Uniprot-TrEMBL)
XCL2 ProteinQ9UBD3 (Uniprot-TrEMBL)
XCR1 ProteinP46094 (Uniprot-TrEMBL)
p-6Y-EGFR ProteinP00533 (Uniprot-TrEMBL)
p-ERK1/2/5R-HSA-199878 (Reactome)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-198746 (Reactome)
ADPArrowR-HSA-199895 (Reactome)
ADRBK1R-HSA-416516 (Reactome)
ATPR-HSA-198746 (Reactome)
ATPR-HSA-199895 (Reactome)
CCKBRR-HSA-870269 (Reactome)
CREB1R-HSA-199895 (Reactome)
DAGArrowR-HSA-114688 (Reactome)
DAGR-HSA-400015 (Reactome)
EGFRR-HSA-2179387 (Reactome)
G-protein alpha (q):GRK2ArrowR-HSA-416516 (Reactome)
G-protein alpha (q):GRK5ArrowR-HSA-416510 (Reactome)
G-protein alpha (q/11): GTPArrowR-HSA-749452 (Reactome)
G-protein alpha (q/11): GTPR-HSA-398188 (Reactome)
G-protein alpha (q/11): GTPR-HSA-400586 (Reactome)
G-protein alpha (q/11): GTPR-HSA-416358 (Reactome)
G-protein alpha (q/11): GTPR-HSA-416510 (Reactome)
G-protein alpha (q/11): GTPR-HSA-416516 (Reactome)
G-protein alpha (q/11): GTPR-HSA-418582 (Reactome)
G-protein alpha (q/11):GDPArrowR-HSA-418582 (Reactome)
G-protein alpha (q/11):GDPR-HSA-750993 (Reactome)
G-protein alpha (q/11):PI3K alphaArrowR-HSA-416358 (Reactome)
G-protein alpha

(q/11):Trio family

RhoGEFs		ArrowR-HSA-400586 (Reactome)
G-protein alpha (q/11)mim-catalysisR-HSA-418582 (Reactome)
G-protein beta-gamma complexArrowR-HSA-749452 (Reactome)
G-protein beta-gamma complexR-HSA-750993 (Reactome)
GAST(76-92)R-HSA-870269 (Reactome)
GDPArrowR-HSA-2179407 (Reactome)
GDPArrowR-HSA-379048 (Reactome)
GPCRs that activate Gq/11ArrowR-HSA-749452 (Reactome)
GRB2-1:SOS1R-HSA-2179415 (Reactome)
GRB2:SOS1:HB-EGF:p-6Y-EGFRArrowR-HSA-2179415 (Reactome)
GRB2:SOS1:HB-EGF:p-6Y-EGFRmim-catalysisR-HSA-2179407 (Reactome)
GRK5R-HSA-416510 (Reactome)
GTPR-HSA-2179407 (Reactome)
GTPR-HSA-379048 (Reactome)
Gastrin:CCKBRArrowR-HSA-870269 (Reactome)
HB-EGF:p-6Y-EGFR dimerArrowR-HSA-2179387 (Reactome)
HB-EGF:p-6Y-EGFR dimerR-HSA-2179415 (Reactome)
HBEGF(149-208)ArrowR-HSA-2179402 (Reactome)
HBEGF(20-208)R-HSA-2179402 (Reactome)
HBEGF(20-62)ArrowR-HSA-2179402 (Reactome)
HBEGF(63-148)ArrowR-HSA-2179402 (Reactome)
HBEGF(63-148)R-HSA-2179387 (Reactome)
Heterotrimeric

G-protein Gq/11

(inactive)		ArrowR-HSA-750993 (Reactome)
Heterotrimeric

G-protein Gq/11

(inactive)		R-HSA-749448 (Reactome)
I(1,4,5)P3ArrowR-HSA-114688 (Reactome)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (active)		ArrowR-HSA-379048 (Reactome)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (active)		R-HSA-749452 (Reactome)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (inactive)		ArrowR-HSA-749448 (Reactome)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (inactive)		R-HSA-379048 (Reactome)
Ligand:GPCR

complexes that activate

Gq/11:Heterotrimeric G-protein Gq (inactive)		mim-catalysisR-HSA-379048 (Reactome)
Ligand:GPCR

complexes that

activate Gq/11		R-HSA-749448 (Reactome)
Ligands of GPCRs that activate Gq/11ArrowR-HSA-749452 (Reactome)
MMP3ArrowR-HSA-2179413 (Reactome)
MMP3mim-catalysisR-HSA-2179402 (Reactome)
PI(4,5)P2R-HSA-114688 (Reactome)
PI3K alphaR-HSA-416358 (Reactome)
PLC beta:G alpha (q/11)ArrowR-HSA-398188 (Reactome)
PLC beta:G alpha (q/11)mim-catalysisR-HSA-114688 (Reactome)
PLC-betaR-HSA-398188 (Reactome)
PRKCAR-HSA-400015 (Reactome)
Phospho-Ribosomal protein S6 kinaseArrowR-HSA-198746 (Reactome)
Phospho-Ribosomal protein S6 kinasemim-catalysisR-HSA-199895 (Reactome)
Protein Kinase C, alpha type: DAGArrowR-HSA-400015 (Reactome)
Protein Kinase C, alpha type: DAGmim-catalysisR-HSA-2179413 (Reactome)
R-HSA-114688 (Reactome) Phospholipase C (PLC) isozymes are a group of related proteins that cleave the polar head group from inositol phospholipids, typically in response to signals from cell surface receptors. They hydrolyze the highly phosphorylated lipid phosphatidylinositol 4,5-bisphosphate (PIP2) generating two products: inositol 1,4,5-trisphosphate (IP3), a universal calcium-mobilizing second messenger, and diacylglycerol (DAG), an activator of protein kinase C. PLC-beta isoforms are regulated by heterotrimeric GTP-binding proteins. PLC-beta 1 and 3 are widely expressed, with the highest concentrations found in (differing) specific regions of the brain. PLC-beta 2 is expressed at highest levels in cells of hematopoeitic origin; it is involved in leukocyte signaling and host defense. PLC-beta 4 is highly concentrated in cerebellar Purkinje and granule cells, the median geniculate body, whose axons terminate in the auditory cortex, and the lateral geniculate nucleus, where most retinal axons terminate in a visuotopic representation of each half of the visual field.
R-HSA-198746 (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.

R-HSA-199895 (Reactome) CREB is phosphorylated at Serine 133 by RSK1/2/3.
R-HSA-2179387 (Reactome) The heparin-binding EGF growth factor (HBEGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor EGFR/ErbB1 and ErbB4 (not shown here) (Higashiyama et al. 1991, Elenius et al. 1997). The details which describe receptor dimerisation on ligand binding and autophosphorylation from experiments in mice have been omitted here.
R-HSA-2179402 (Reactome) Gastrin can induce cleavage of pro-HBEGF via MMP3, releasing mature HBEGF. This event is based on evidence from mouse experiments (Suzuki et al. 1997).
R-HSA-2179407 (Reactome) SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP) (Chardin et al. 1993).
R-HSA-2179413 (Reactome) Gastrin activated PKC pathway leads to the induction of matrix metalloproteinase 3 (MMP3) synthesis (Reuben et al. 2002). The cleavage and autocatalysis steps to obtain the fully activated form of MMP3 have been omitted here.
R-HSA-2179415 (Reactome) Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 autophosphorylation sites on the receptor (Batzer et al. 1994, Okutani et al. 1994).
R-HSA-379048 (Reactome) G alpha q protein (or Gq/11) consists of four family members (G-alpha 11, -alpha 14, -alpha 15 and -alpha q). It activates phospholipase C (PLC) (Dowal L et al, 2006). PLC hydrolyzes phosphatidylinositol (PIP2) to diacyl glycerol (DAG) and inositol triphosphate (IP3). DAG acts as a second messenger that activates protein kinase C (PKC) and IP3 can bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). Calcium flow causes the cytosolic concentration of calcium to increase, causing a cascade of intracellular changes and activity.
R-HSA-398188 (Reactome) The active form of G protein alpha subunit q (Gq-alpha) was found to activate phospholipase C beta-1 (PLC-beta1), in investigations using bovine membranes. Subsequently, all 4 human isoforms have been shown to be activated by Gq, though activation of PLCbeta-4 is limited. In recombinant assays, several activated rat G alpha q family members were found to stimulate human PLC-beta isoforms with the same rank order of decreasing potency. PLC-beta1 stimulation was slightly more than for PLC-beta3; PLC-beta3 stimulation was 10-fold greater than for beta-2. PLC-beta2 is expressed specifically in hematopoietic cells. PLC-beta acts directly on Gq to accelerate hydrolysis of bound GTP, thus PLC-betas are GTPase activating proteins (GAPs). The crystal structure of the C-terminal region from Turkey PLC-beta, revealed a novel fold composed almost entirely of three long helices forming a coiled-coil that dimerizes along its long axis in an antiparallel orientation. The extent of the dimer interface and gel exclusion chromatography data suggest that PLC-betas are functionally dimeric.
R-HSA-400015 (Reactome) Diacylglycerol, produced by PLC beta-mediated PIP2 hydrolysis in G alpha (q) signalling, remains in the plasma membrane and binds Protein Kinase C alpha (PKC-alpha), causing PKC-alpha to translocate from the cytosol to the plasma membrane. PKC-alpha is thereby activated and phosphorylates target proteins.
R-HSA-400586 (Reactome) The Trio family of RhoA guanine nucleotide exchange factors (RhoGEFs) are directly activated by G alpha (q), possibly within a Gq:Trio:RhoA signalling complex, thereby linking Gq to RhoA-mediated processes such as cell migration, proliferation, and contraction. Like most other RhoGEFs, they have a tandem motif consisting of a Dbl homology (DH) and a pleckstrin homology (PH) domain. Trio and Duet have a number of other domains including an immunoglobin domains that may be involved in interacting with Rho, but the considerably smaller GEFT (p63RhoGEF) does not have any identifiable additional domains yet appears to be sufficient to mediate the activation of RhoA by G alpha (q). The structure represented by GEFT is proposed to represent the core of an ancient signal transduction pathway.
R-HSA-416358 (Reactome) Phospholipase C activation is the classical signalling route for G alpha (q) but an additional mechanism is an inhibitory interaction between G alpha (q) and phosphatidylinositol 3-kinase alpha (PI3K alpha). There are several PI3K subtypes but only the p85 alpha/p110 alpha subtype (PI3K alpha) is a G alpha (q) effector (PMID: 18515384). Activated G alpha (q) inhibits PI3K alpha directly, in a GTP-dependent manner. G alpha(q) binding of PI3K competes with Ras, a PI3K activator (PMID: 16268778).
R-HSA-416510 (Reactome) GRKs are serine/threonine kinases that phosphorylate GPCRs leading to receptor desensitization. GRK5 appears to be the predominant regulator of PAR1 desensitization in endothelial cells.
R-HSA-416516 (Reactome) GRK2 can inhibit GPCR signaling via phosphorylation-independent sequestration of Gq/11/14 subunits utilising its RGS homology (RH) domain. GRK2 may be an effector of activated Gq, initiating signalling cascades other than the classical PLC beta signalling associated with Gq.
R-HSA-418582 (Reactome) When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region.
R-HSA-749448 (Reactome) Numerous functionally unrelated GPCRs couple with the Gq G-protein subtype.
R-HSA-749452 (Reactome) The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (q) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
R-HSA-750993 (Reactome) The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (q) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (q):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates.
R-HSA-870269 (Reactome) Gastrin receptors (gastric cholecystokinin B receptor, CCK-BR) mediate acid secretion from parietal cells, release of histamine from enterochromaffin-like (ECL) cells and contraction of smooth muscle (Ito et al. 1993).The hormone gastrin is the central regulator of gastric acid secretion and in addition, plays a prominent role in regulation of growth and differentiation of gastric and colonic mucosa.
RGS proteins active for G alpha (q)ArrowR-HSA-418582 (Reactome)
Ribosomal protein S6 kinaseR-HSA-198746 (Reactome)
TRIO family RhoGEFsR-HSA-400586 (Reactome)
p-ERK1/2/5mim-catalysisR-HSA-198746 (Reactome)
p-S133-CREB1ArrowR-HSA-199895 (Reactome)
p21 RAS:GDPR-HSA-2179407 (Reactome)
p21 RAS:GTPArrowR-HSA-2179407 (Reactome)
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