KEGG   PATHWAY: hsa04015Help
Entry
hsa04015                    Pathway                                

Name
Rap1 signaling pathway - Homo sapiens (human)
Description
Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.
Class
Environmental Information Processing; Signal transduction
BRITE hierarchy
Pathway map
hsa04015  Rap1 signaling pathway
hsa04015

Ortholog table
Disease
H00505  FGFR3-related short limb skeletal dysplasia
H00535  Hereditary lymphedema
H02068  Hypochondroplasia
H02069  SADDAN
Drug
D10224  Golvatinib (USAN)
D10374  Lifitegrast (USAN/INN)
D10392  Lifitegrast sodium (USAN)
D10465  Golvatinib tartrate (USAN)
Other DBs
BSID: 868086
GO: 0007264
Organism
Homo sapiens (human) [GN:hsa]
Gene
5906  RAP1A; RAP1A, member of RAS oncogene family [KO:K04353]
5908  RAP1B; RAP1B, member of RAS oncogene family [KO:K07836]
22808  MRAS; muscle RAS oncogene homolog [KO:K07831]
9771  RAPGEF5; Rap guanine nucleotide exchange factor 5 [KO:K08019]
9732  DOCK4; dedicator of cytokinesis 4 [KO:K17697]
2902  GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208]
2903  GRIN2A; glutamate ionotropic receptor NMDA type subunit 2A [KO:K05209]
2904  GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210]
810  CALML3; calmodulin like 3 [KO:K02183]
805  CALM2; calmodulin 2 [KO:K02183]
808  CALM3; calmodulin 3 [KO:K02183]
801  CALM1; calmodulin 1 [KO:K02183]
163688  CALML6; calmodulin like 6 [KO:K02183]
51806  CALML5; calmodulin like 5 [KO:K02183]
91860  CALML4; calmodulin like 4 [KO:K02183]
2149  F2R; coagulation factor II thrombin receptor [KO:K03914]
9002  F2RL3; F2R like thrombin or trypsin receptor 3 [KO:K04236]
5028  P2RY1; purinergic receptor P2Y1 [KO:K04270]
2357  FPR1; formyl peptide receptor 1 [KO:K04172]
1902  LPAR1; lysophosphatidic acid receptor 1 [KO:K04289]
9170  LPAR2; lysophosphatidic acid receptor 2 [KO:K04291]
23566  LPAR3; lysophosphatidic acid receptor 3 [KO:K04294]
2846  LPAR4; lysophosphatidic acid receptor 4 [KO:K04275]
57121  LPAR5; lysophosphatidic acid receptor 5 [KO:K08390]
135  ADORA2A; adenosine A2a receptor [KO:K04266]
136  ADORA2B; adenosine A2b receptor [KO:K04267]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
10411  RAPGEF3; Rap guanine nucleotide exchange factor 3 [KO:K08014]
11069  RAPGEF4; Rap guanine nucleotide exchange factor 4 [KO:K04351]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
25780  RASGRP3; RAS guanyl releasing protein 3 [KO:K12362]
10235  RASGRP2; RAS guanyl releasing protein 2 [KO:K12361]
1950  EGF; epidermal growth factor [KO:K04357]
2246  FGF1; fibroblast growth factor 1 [KO:K18496]
2247  FGF2; fibroblast growth factor 2 [KO:K18497]
2248  FGF3; fibroblast growth factor 3 [KO:K04358]
2249  FGF4; fibroblast growth factor 4 [KO:K04358]
8822  FGF17; fibroblast growth factor 17 [KO:K04358]
2251  FGF6; fibroblast growth factor 6 [KO:K04358]
2252  FGF7; fibroblast growth factor 7 [KO:K04358]
2253  FGF8; fibroblast growth factor 8 [KO:K04358]
2254  FGF9; fibroblast growth factor 9 [KO:K04358]
2255  FGF10; fibroblast growth factor 10 [KO:K04358]
8823  FGF16; fibroblast growth factor 16 [KO:K04358]
2250  FGF5; fibroblast growth factor 5 [KO:K04358]
8817  FGF18; fibroblast growth factor 18 [KO:K04358]
26281  FGF20; fibroblast growth factor 20 [KO:K04358]
27006  FGF22; fibroblast growth factor 22 [KO:K04358]
9965  FGF19; fibroblast growth factor 19 [KO:K22603]
26291  FGF21; fibroblast growth factor 21 [KO:K22429]
8074  FGF23; fibroblast growth factor 23 [KO:K22428]
4803  NGF; nerve growth factor [KO:K02582]
3630  INS; insulin [KO:K04526]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
5154  PDGFA; platelet derived growth factor subunit A [KO:K04359]
5155  PDGFB; platelet derived growth factor subunit B [KO:K17386]
56034  PDGFC; platelet derived growth factor C [KO:K05450]
80310  PDGFD; platelet derived growth factor D [KO:K05450]
1435  CSF1; colony stimulating factor 1 [KO:K05453]
4254  KITLG; KIT ligand [KO:K05461]
7422  VEGFA; vascular endothelial growth factor A [KO:K05448]
7423  VEGFB; vascular endothelial growth factor B [KO:K16858]
5228  PGF; placental growth factor [KO:K16859]
7424  VEGFC; vascular endothelial growth factor C [KO:K05449]
2277  VEGFD; vascular endothelial growth factor D [KO:K05449]
3082  HGF; hepatocyte growth factor [KO:K05460]
284  ANGPT1; angiopoietin 1 [KO:K05465]
285  ANGPT2; angiopoietin 2 [KO:K05466]
51378  ANGPT4; angiopoietin 4 [KO:K05467]
1942  EFNA1; ephrin A1 [KO:K05462]
1943  EFNA2; ephrin A2 [KO:K05462]
1944  EFNA3; ephrin A3 [KO:K05462]
1945  EFNA4; ephrin A4 [KO:K05462]
1946  EFNA5; ephrin A5 [KO:K05462]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2260  FGFR1; fibroblast growth factor receptor 1 [KO:K04362] [EC:2.7.10.1]
2263  FGFR2; fibroblast growth factor receptor 2 [KO:K05093] [EC:2.7.10.1]
2261  FGFR3; fibroblast growth factor receptor 3 [KO:K05094] [EC:2.7.10.1]
2264  FGFR4; fibroblast growth factor receptor 4 [KO:K05095] [EC:2.7.10.1]
4804  NGFR; nerve growth factor receptor [KO:K02583]
3643  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
3480  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
5156  PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
5159  PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
1436  CSF1R; colony stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]
3815  KIT; KIT proto-oncogene receptor tyrosine kinase [KO:K05091] [EC:2.7.10.1]
2321  FLT1; fms related tyrosine kinase 1 [KO:K05096] [EC:2.7.10.1]
2324  FLT4; fms related tyrosine kinase 4 [KO:K05097] [EC:2.7.10.1]
3791  KDR; kinase insert domain receptor [KO:K05098] [EC:2.7.10.1]
4233  MET; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:2.7.10.1]
7010  TEK; TEK receptor tyrosine kinase [KO:K05121] [EC:2.7.10.1]
1969  EPHA2; EPH receptor A2 [KO:K05103] [EC:2.7.10.1]
1398  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
1399  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
2889  RAPGEF1; Rap guanine nucleotide exchange factor 1 [KO:K06277]
9564  BCAR1; BCAR1, Cas family scaffold protein [KO:K05726]
999  CDH1; cadherin 1 [KO:K05689]
1499  CTNNB1; catenin beta 1 [KO:K02105]
9223  MAGI1; membrane associated guanylate kinase, WW and PDZ domain containing 1 [KO:K05631]
9863  MAGI2; membrane associated guanylate kinase, WW and PDZ domain containing 2 [KO:K05629]
260425  MAGI3; membrane associated guanylate kinase, WW and PDZ domain containing 3 [KO:K06112]
9693  RAPGEF2; Rap guanine nucleotide exchange factor 2 [KO:K08018]
51735  RAPGEF6; Rap guanine nucleotide exchange factor 6 [KO:K08020]
27040  LAT; linker for activation of T cells [KO:K07362]
2533  FYB1; FYN binding protein 1 [KO:K17698]
3937  LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
8631  SKAP1; src kinase associated phosphoprotein 1 [KO:K17699]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
5587  PRKD1; protein kinase D1 [KO:K06070] [EC:2.7.11.13]
23683  PRKD3; protein kinase D3 [KO:K06070] [EC:2.7.11.13]
25865  PRKD2; protein kinase D2 [KO:K06070] [EC:2.7.11.13]
1813  DRD2; dopamine receptor D2 [KO:K04145]
1268  CNR1; cannabinoid receptor 1 [KO:K04277]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
2775  GNAO1; G protein subunit alpha o1 [KO:K04534]
5909  RAP1GAP; RAP1 GTPase activating protein [KO:K17700]
26037  SIPA1L1; signal induced proliferation associated 1 like 1 [KO:K17701]
6494  SIPA1; signal-induced proliferation-associated 1 [KO:K08013]
57568  SIPA1L2; signal induced proliferation associated 1 like 2 [KO:K17702]
23094  SIPA1L3; signal induced proliferation associated 1 like 3 [KO:K17703]
3397  ID1; inhibitor of DNA binding 1, HLH protein [KO:K04680]
7057  THBS1; thrombospondin 1 [KO:K16857]
5900  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
5898  RALA; RAS like proto-oncogene A [KO:K07834]
5899  RALB; RAS like proto-oncogene B [KO:K07835]
5879  RAC1; Rac family small GTPase 1 [KO:K04392]
5880  RAC2; Rac family small GTPase 2 [KO:K07860]
5881  RAC3; Rac family small GTPase 3 [KO:K07861]
54518  APBB1IP; amyloid beta precursor protein binding family B member 1 interacting protein [KO:K17704]
7094  TLN1; talin 1 [KO:K06271]
83660  TLN2; talin 2 [KO:K06271]
3674  ITGA2B; integrin subunit alpha 2b [KO:K06476]
3690  ITGB3; integrin subunit beta 3 [KO:K06493]
345456  PFN3; profilin 3 [KO:K05759]
5216  PFN1; profilin 1 [KO:K05759]
5217  PFN2; profilin 2 [KO:K05759]
375189  PFN4; profilin family member 4 [KO:K05759]
7408  VASP; vasodilator stimulated phosphoprotein [KO:K06274]
60  ACTB; actin beta [KO:K05692]
71  ACTG1; actin gamma 1 [KO:K05692]
64411  ARAP3; ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 3 [KO:K12490]
387  RHOA; ras homolog family member A [KO:K04513]
6714  SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
9855  FARP2; FERM, ARH/RhoGEF and pleckstrin domain protein 2 [KO:K06082]
998  CDC42; cell division cycle 42 [KO:K04393]
7074  TIAM1; T cell lymphoma invasion and metastasis 1 [KO:K05731]
56288  PARD3; par-3 family cell polarity regulator [KO:K04237]
50855  PARD6A; par-6 family cell polarity regulator alpha [KO:K06093]
84552  PARD6G; par-6 family cell polarity regulator gamma [KO:K06093]
84612  PARD6B; par-6 family cell polarity regulator beta [KO:K06093]
5590  PRKCZ; protein kinase C zeta [KO:K18952] [EC:2.7.11.13]
5584  PRKCI; protein kinase C iota [KO:K06069] [EC:2.7.11.13]
4301  AFDN; afadin, adherens junction formation factor [KO:K05702]
1500  CTNND1; catenin delta 1 [KO:K05690]
889  KRIT1; KRIT1, ankyrin repeat containing [KO:K17705]
10636  RGS14; regulator of G protein signaling 14 [KO:K17706]
83593  RASSF5; Ras association domain family member 5 [KO:K08015]
3683  ITGAL; integrin subunit alpha L [KO:K05718]
3684  ITGAM; integrin subunit alpha M [KO:K06461]
3689  ITGB2; integrin subunit beta 2 [KO:K06464]
3688  ITGB1; integrin subunit beta 1 [KO:K05719]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
51196  PLCE1; phospholipase C epsilon 1 [KO:K05860] [EC:3.1.4.11]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
6237  RRAS; RAS related [KO:K07829]
7410  VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730]
Compound
C00035  GDP
C00044  GTP
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
Reference
  Authors
Kooistra MR, Dube N, Bos JL
  Title
Rap1: a key regulator in cell-cell junction formation.
  Journal
J Cell Sci 120:17-22 (2007)
DOI:10.1242/jcs.03306
Reference
  Authors
Bos JL, de Rooij J, Reedquist KA
  Title
Rap1 signalling: adhering to new models.
  Journal
Nat Rev Mol Cell Biol 2:369-77 (2001)
DOI:10.1038/35073073
Reference
  Authors
Minato N, Kometani K, Hattori M
  Title
Regulation of immune responses and hematopoiesis by the Rap1 signal.
  Journal
Adv Immunol 93:229-64 (2007)
DOI:10.1016/S0065-2776(06)93006-5
Reference
  Authors
Bos JL
  Title
Linking Rap to cell adhesion.
  Journal
Curr Opin Cell Biol 17:123-8 (2005)
DOI:10.1016/j.ceb.2005.02.009
Reference
  Authors
Caron E
  Title
Cellular functions of the Rap1 GTP-binding protein: a pattern emerges.
  Journal
J Cell Sci 116:435-40 (2003)
DOI:10.1242/jcs.00238
Reference
  Authors
Zwartkruis FJ, Bos JL
  Title
Ras and Rap1: two highly related small GTPases with distinct function.
  Journal
Exp Cell Res 253:157-65 (1999)
DOI:10.1006/excr.1999.4695
Reference
  Authors
Hattori M, Minato N
  Title
Rap1 GTPase: functions, regulation, and malignancy.
  Journal
J Biochem 134:479-84 (2003)
DOI:10.1093/jb/mvg180
Reference
  Authors
Pannekoek WJ, Kooistra MR, Zwartkruis FJ, Bos JL
  Title
Cell-cell junction formation: the role of Rap1 and Rap1 guanine nucleotide exchange factors.
  Journal
Biochim Biophys Acta 1788:790-6 (2009)
DOI:10.1016/j.bbamem.2008.12.010
Reference
  Authors
Boettner B, Van Aelst L
  Title
Control of cell adhesion dynamics by Rap1 signaling.
  Journal
Curr Opin Cell Biol 21:684-93 (2009)
DOI:10.1016/j.ceb.2009.06.004
Reference
  Authors
Xia Z, Storm DR.
  Title
The role of calmodulin as a signal integrator for synaptic plasticity.
  Journal
Nat Rev Neurosci 6:267-76 (2005)
DOI:10.1038/nrn1647
Reference
  Authors
Mor A, Dustin ML, Philips MR
  Title
Small GTPases and LFA-1 reciprocally modulate adhesion and signaling.
  Journal
Immunol Rev 218:114-25 (2007)
DOI:10.1111/j.1600-065X.2007.00538.x
Reference
  Authors
Burbach BJ, Medeiros RB, Mueller KL, Shimizu Y
  Title
T-cell receptor signaling to integrins.
  Journal
Immunol Rev 218:65-81 (2007)
DOI:10.1111/j.1600-065X.2007.00527.x
Reference
  Authors
Stork PJ
  Title
Does Rap1 deserve a bad Rap?
  Journal
Trends Biochem Sci 28:267-75 (2003)
DOI:10.1016/S0968-0004(03)00087-2
Reference
  Authors
Banihashemi B, Albert PR
  Title
Dopamine-D2S receptor inhibition of calcium influx, adenylyl cyclase, and mitogen-activated protein kinase in pituitary cells: distinct Galpha and Gbetagamma requirements.
  Journal
Mol Endocrinol 16:2393-404 (2002)
DOI:10.1210/me.2001-0220
Reference
  Authors
Banno A, Ginsberg MH
  Title
Integrin activation.
  Journal
Biochem Soc Trans 36:229-34 (2008)
DOI:10.1042/BST0360229
Reference
  Authors
Doebele RC, Schulze-Hoepfner FT, Hong J, Chlenski A, Zeitlin BD, Goel K, Gomes S, Liu Y, Abe MK, Nor JE, Lingen MW, Rosner MR
  Title
A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesis.
  Journal
Blood 114:4592-600 (2009)
DOI:10.1182/blood-2009-04-217042
Reference
  Authors
Breckler M, Berthouze M, Laurent AC, Crozatier B, Morel E, Lezoualc'h F
  Title
Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications.
  Journal
Cell Signal 23:1257-66 (2011)
DOI:10.1016/j.cellsig.2011.03.007
KO pathway
ko04015   

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