Rap1 signaling (Homo sapiens)

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32-4, 82-4, 811961, 105, 7, 9cytosolRAP1GAP2Rap1-GTP:Raf1ATPGTP p-S7-RAP1GAP2RAF1RAPGEF3 Rap1 cAMP-GEFsRAP1GAP2 GTPcAMPRap1-GTPRAP1B YWHAZ RASGRP2 RAPGEF3 RAPGEF4 YWHAB RAF1 PPiRap1 cAMP-GEFs:cAMPRAP1B GDPRAP1A ADPRap1-GDPRAP1GAP Rap1GTPase-activatingproteinsSIPA1 YWHAZ RAP1A 14-3-3 beta, zetaCalDAG-GEFsRAP1A cAMP GDP PKA catalyticsubunits, PKG typeIRAPGEF4 RAP1B RAP1GAP2 PRKG1-1 RAP1GAP2:14-3-3beta,zetaYWHAB RASGRP1 GTP Protein Kinase A, catalytic subunits


Description

Rap1 (Ras-proximate-1) is a small G protein in the Ras superfamily. Like all G proteins, Rap1 is activated when bound GDP is exchanged for GTP. Rap1 is targeted to lipid membranes by the covalent attachment of lipid moieties to its carboxyl terminus. Movement of Rap1 from endosomal membranes to the plasma membrane upon activation has been reported in several cell types including Jurkat T cells and megakaryocytes. On activation, Rap1 undergoes conformational changes that facilitate recruitment of a variety of effectors, triggering it's participation in integrin signaling, ERK activation, and others. View original pathway at:Reactome.

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Bibliography

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  1. Stork PJ, Dillon TJ.; ''Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions.''; PubMed Europe PMC Scholia
  2. Schultess J, Danielewski O, Smolenski AP.; ''Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets.''; PubMed Europe PMC Scholia
  3. Hoffmeister M, Riha P, Neumüller O, Danielewski O, Schultess J, Smolenski AP.; ''Cyclic nucleotide-dependent protein kinases inhibit binding of 14-3-3 to the GTPase-activating protein Rap1GAP2 in platelets.''; PubMed Europe PMC Scholia
  4. Polakis PG, Rubinfeld B, Evans T, McCormick F.; ''Purification of a plasma membrane-associated GTPase-activating protein specific for rap1/Krev-1 from HL60 cells.''; PubMed Europe PMC Scholia
  5. Kawasaki H, Springett GM, Toki S, Canales JJ, Harlan P, Blumenstiel JP, Chen EJ, Bany IA, Mochizuki N, Ashbacher A, Matsuda M, Housman DE, Graybiel AM.; ''A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia.''; PubMed Europe PMC Scholia
  6. Kurachi H, Wada Y, Tsukamoto N, Maeda M, Kubota H, Hattori M, Iwai K, Minato N.; ''Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product.''; PubMed Europe PMC Scholia
  7. Lafuente E, Boussiotis VA.; ''Rap1 regulation of RIAM and cell adhesion.''; PubMed Europe PMC Scholia
  8. Cook SJ, Rubinfeld B, Albert I, McCormick F.; ''RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts.''; PubMed Europe PMC Scholia
  9. Hu CD, Kariya Ki, Kotani G, Shirouzu M, Yokoyama S, Kataoka T.; ''Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1.''; PubMed Europe PMC Scholia
  10. Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, Housman DE, Graybiel AM.; ''CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation.''; PubMed Europe PMC Scholia
  11. Lafuente EM, van Puijenbroek AA, Krause M, Carman CV, Freeman GJ, Berezovskaya A, Constantine E, Springer TA, Gertler FB, Boussiotis VA.; ''RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
116417view09:09, 7 May 2021EweitzModified title
114768view16:25, 25 January 2021ReactomeTeamReactome version 75
113212view11:28, 2 November 2020ReactomeTeamReactome version 74
112436view15:38, 9 October 2020ReactomeTeamReactome version 73
101341view11:22, 1 November 2018ReactomeTeamreactome version 66
100879view20:56, 31 October 2018ReactomeTeamreactome version 65
100420view19:30, 31 October 2018ReactomeTeamreactome version 64
99970view16:14, 31 October 2018ReactomeTeamreactome version 63
99524view14:49, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99164view12:41, 31 October 2018ReactomeTeamreactome version 62
93990view13:49, 16 August 2017ReactomeTeamreactome version 61
93596view11:28, 9 August 2017ReactomeTeamreactome version 61
88130view10:18, 26 July 2016RyanmillerOntology Term : 'signaling pathway in the adaptive immune response' added !
88129view10:17, 26 July 2016RyanmillerOntology Term : 'Ras superfamily mediated signaling pathway' added !
88128view10:16, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86703view09:24, 11 July 2016ReactomeTeamreactome version 56
83370view11:01, 18 November 2015ReactomeTeamVersion54
81536view13:04, 21 August 2015ReactomeTeamVersion53
77004view08:29, 17 July 2014ReactomeTeamFixed remaining interactions
76709view12:07, 16 July 2014ReactomeTeamFixed remaining interactions
76035view10:09, 11 June 2014ReactomeTeamRe-fixing comment source
75744view11:23, 10 June 2014ReactomeTeamReactome 48 Update
75094view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74741view08:49, 30 April 2014ReactomeTeamReactome46
42111view21:57, 4 March 2011MaintBotAutomatic update
39921view05:56, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14-3-3 beta, zetaComplexR-HSA-914001 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CalDAG-GEFsComplexR-HSA-392488 (Reactome) Rap1 can be activated by certain GEFs that respond to calcium and diacylglycerol (CalDAG-GEFs).
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
PKA catalytic

subunits, PKG type

I		ComplexR-HSA-913988 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKG1-1 ProteinQ13976-1 (Uniprot-TrEMBL)
Protein Kinase A, catalytic subunits R-HSA-913999 (Reactome)
RAF1 ProteinP04049 (Uniprot-TrEMBL)
RAF1ProteinP04049 (Uniprot-TrEMBL)
RAP1A ProteinP62834 (Uniprot-TrEMBL)
RAP1B ProteinP61224 (Uniprot-TrEMBL)
RAP1GAP ProteinP47736 (Uniprot-TrEMBL)
RAP1GAP2 ProteinQ684P5 (Uniprot-TrEMBL)
RAP1GAP2:14-3-3beta, zetaComplexR-HSA-913992 (Reactome)
RAP1GAP2ProteinQ684P5 (Uniprot-TrEMBL)
RAPGEF3 ProteinO95398 (Uniprot-TrEMBL)
RAPGEF4 ProteinQ8WZA2 (Uniprot-TrEMBL)
RASGRP1 ProteinO95267 (Uniprot-TrEMBL)
RASGRP2 ProteinQ7LDG7 (Uniprot-TrEMBL)
Rap1

GTPase-activating

proteins		ComplexR-HSA-392497 (Reactome)
Rap1 cAMP-GEFs:cAMPComplexR-HSA-392837 (Reactome)
Rap1 cAMP-GEFsComplexR-HSA-392485 (Reactome)
Rap1-GDPComplexR-HSA-354074 (Reactome)
Rap1-GTP:Raf1ComplexR-HSA-430243 (Reactome)
Rap1-GTPComplexR-HSA-354126 (Reactome)
SIPA1 ProteinQ96FS4 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
cAMP MetaboliteCHEBI:17489 (ChEBI)
cAMPMetaboliteCHEBI:17489 (ChEBI)
p-S7-RAP1GAP2ProteinQ684P5 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
14-3-3 beta, zetaR-HSA-913993 (Reactome)
ADPArrowR-HSA-913996 (Reactome)
ATPR-HSA-913996 (Reactome)
CalDAG-GEFsmim-catalysisR-HSA-354173 (Reactome)
GDPArrowR-HSA-354173 (Reactome)
GDPArrowR-HSA-939265 (Reactome)
GTPR-HSA-354173 (Reactome)
GTPR-HSA-939265 (Reactome)
PKA catalytic

subunits, PKG type

I		mim-catalysisR-HSA-913996 (Reactome)
PPiArrowR-HSA-392513 (Reactome)
R-HSA-354173 (Reactome) Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP.
R-HSA-392513 (Reactome) Rap1 signalling is terminated by the hydrolysis of bound GTP to GDP. The intrinsic GTPase activity of Rap1 is greatly enhanced by GTP-ase activating proteins (GAPs).
R-HSA-392834 (Reactome) EPACs (exchange proteins directly activated by cAMP) are Rap1 GEFs that are activated by direct binding of cAMP (cyclic adenosine monophosphate). cAMP-GEFI (EPAC1) is widely expressed, while cAMP-GEFII (EPAC2) is enriched in brain and adrenal tissue. Both are selective for Rap1. A role of EPACs has been proposed for Rap1-dependent cell adhesion to laminin in both epithelial and red blood cells, and in the regulation of vascular endothelial barrier function.
R-HSA-392835 (Reactome) Active Rap1 binds but does not activate Raf-1, preventing Raf-1 from participating in the Ras/ERK pathway.
R-HSA-913993 (Reactome) RAP1GAP2 binds 14-3-3 proteins beta and zeta, inhibiting its GAP activity for Rap1. This effect is diminished by Ser-7 phosphorylation of RAP1GAP2 by cGMP- and cAMP-dependent protein kinases (PKG and PKA respectively), which inhibits the binding of 14-3-3 proteins beta and zeta to Rap1GAP2. 14-3-3 binding does not appear to alter the GTPase-activating function of Rap1GAP2 in vitro, but attenuates Rap1GAP2 mediated inhibition of cell adhesion (Hoffmeister et al. 2008).
R-HSA-913996 (Reactome) cGMP and cAMP dependent protein kinases (PKG and PKA respectively) phosphorylate the Rap1 GTPase activating RAP1GAP2 at serine 7 (Schultess et al. 2007). This reduces the binding of inhibitory 14-3-3 proteins to RAP1GAP2.
R-HSA-939265 (Reactome) Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP.
RAF1R-HSA-392835 (Reactome)
RAP1GAP2:14-3-3beta, zetaArrowR-HSA-913993 (Reactome)
RAP1GAP2:14-3-3beta, zetaTBarR-HSA-392513 (Reactome)
RAP1GAP2R-HSA-913993 (Reactome)
RAP1GAP2R-HSA-913996 (Reactome)
Rap1

GTPase-activating

proteins		mim-catalysisR-HSA-392513 (Reactome)
Rap1 cAMP-GEFs:cAMPArrowR-HSA-392834 (Reactome)
Rap1 cAMP-GEFsR-HSA-392834 (Reactome)
Rap1 cAMP-GEFsmim-catalysisR-HSA-939265 (Reactome)
Rap1-GDPArrowR-HSA-392513 (Reactome)
Rap1-GDPR-HSA-354173 (Reactome)
Rap1-GDPR-HSA-939265 (Reactome)
Rap1-GTP:Raf1ArrowR-HSA-392835 (Reactome)
Rap1-GTPArrowR-HSA-354173 (Reactome)
Rap1-GTPArrowR-HSA-939265 (Reactome)
Rap1-GTPR-HSA-392513 (Reactome)
Rap1-GTPR-HSA-392835 (Reactome)
cAMPR-HSA-392834 (Reactome)
p-S7-RAP1GAP2ArrowR-HSA-913996 (Reactome)
p-S7-RAP1GAP2TBarR-HSA-913993 (Reactome)
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