KEGG   PATHWAY: oaa04926
Entry
oaa04926                    Pathway                                
Name
Relaxin signaling pathway - Ornithorhynchus anatinus (platypus)
Description
Human relaxin-2 ("relaxin"), originally identified as a peptidic hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic and angiogenic effects in both males and females. It belongs to the so-called relaxin peptide family which includes the insulin-like peptides INSL3 and INSL5, and relaxin-3 (H3) as well as relaxin. INSL3 has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. These members of relaxin peptide family exert such effects binding to different kinds of receptors, classified as relaxin family peptide (RXFP) receptors: RXFP1, RXFP2, RXFP3, and RXFP4. These G protein-coupled receptors predominantly bind relaxin, INSL3, relaxin-3, and INSL-5, respectively. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Both RXFP3 and RXFP4 inhibit cAMP production, and RXFP3 activate MAP kinases.
Class
Organismal Systems; Endocrine system
Pathway map
oaa04926  Relaxin signaling pathway
oaa04926

Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
100074095  RFLB; relaxin family locus B precursor [KO:K21998]
100091007  RXFP1; relaxin receptor 1 isoform X1 [KO:K04306]
100079602  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100075665  GNAI1; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100089995  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100077742  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
100080392  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100077049  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
114807890  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100090311  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
100073829  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100081114  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100084993  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100082845  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
114805646  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100092247  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
100076953  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
100088135  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
100081252  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
114813799  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11-like [KO:K04546]
100078907  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
100081920  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
100085219  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100077961  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
114815157  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
114811232  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100078846  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100088079  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
100093310  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100077942  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100089902  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100078176  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100092528  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100076562  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
103165821  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100080655  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
100080771  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100077009  VEGFA; vascular endothelial growth factor A [KO:K05448]
100082290  VEGFD; vascular endothelial growth factor D [KO:K05449]
100084886  VEGFC; vascular endothelial growth factor C [KO:K05449]
100090081  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100083819  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100074633  RELA; transcription factor p65 isoform X1 [KO:K04735]
100075386  NOS2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
100086270  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100073788  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100074273  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100080187  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
100082075  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
103167126  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100089779  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100089456  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100080362  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100087942  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100085480  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100086487  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100077120  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
103166153  epididymal sperm-binding protein 1-like [KO:K01398] [EC:3.4.24.24]
100083320  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100081473  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100090267  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100091599  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
100093259  NOS1; LOW QUALITY PROTEIN: nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
100084367  EDN1; endothelin-1 [KO:K16366]
100084359  endothelin receptor type B-like [KO:K04198]
103170233  EDNRB; endothelin receptor type B [KO:K04198]
100078975  interstitial collagenase isoform X1 [KO:K01388] [EC:3.4.24.7]
100078901  collagenase 3-like [KO:K07994] [EC:3.4.24.-]
100078875  collagenase 3-like isoform X1 [KO:K07994] [EC:3.4.24.-]
114812005  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
100092358  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
100076965  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
100074413  ACTA2; actin, aortic smooth muscle [KO:K12313]
100681278  COL1A2; collagen alpha-2(I) chain [KO:K06236]
100078516  COL27A1; collagen alpha-1(XXVII) chain [KO:K06236]
100079519  COL1A1; collagen alpha-1(I) chain [KO:K06236]
100080810  COL3A1; collagen alpha-1(III) chain [KO:K19720]
100084401  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
100073948  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
100084415  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
100078067  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
100078102  COL4A6; collagen alpha-6(IV) chain [KO:K06237]
103170730  COL4A3; collagen alpha-3(IV) chain isoform X1 [KO:K06237]
100079745  RXFP2; relaxin receptor 2 [KO:K04307]
100078305  RLN3; relaxin-3 precursor [KO:K22000]
100088566  RXFP3; relaxin-3 receptor 1 [KO:K08397]
103168601  ADCY1; LOW QUALITY PROTEIN: adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100089708  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100085901  ADCY3; LOW QUALITY PROTEIN: adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
103168714  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100081118  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
100076221  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100077908  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100080569  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100078508  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100084272  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100081349  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100086536  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100079107  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100091407  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
100089737  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X3 [KO:K04431] [EC:2.7.12.2]
100078507  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
100091330  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
100092264  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100093026  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100073424  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100076033  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
100082590  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100075021  FOS; proto-oncogene c-Fos [KO:K04379]
114809992  HRAS; GTPase HRas [KO:K02833]
100085430  KRAS; GTPase KRas isoform X1 [KO:K07827]
100074671  NRAS; GTPase NRas [KO:K07828]
107547224  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
114808180  SHC1; SHC-transforming protein 1 [KO:K06279]
100081397  SHC2; SHC-transforming protein 2 [KO:K17447]
100084645  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100078989  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100086715  ARRB1; beta-arrestin-1 [KO:K04439]
100084244  ARRB2; beta-arrestin-2 [KO:K04439]
100075894  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100075806  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100085240  GNA15; guanine nucleotide-binding protein subunit alpha-15 [KO:K04637]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00533  Nitric oxide
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:23303914
  Authors
Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ
  Title
Relaxin family peptides and their receptors.
  Journal
Physiol Rev 93:405-80 (2013)
DOI:10.1152/physrev.00001.2012
Reference
PMID:23401142
  Authors
Cernaro V, Lacquaniti A, Lupica R, Buemi A, Trimboli D, Giorgianni G, Bolignano D, Buemi M
  Title
Relaxin: new pathophysiological aspects and pharmacological perspectives for an old protein.
  Journal
Med Res Rev 34:77-105 (2014)
DOI:10.1002/med.21277
Reference
PMID:18675759
  Authors
van der Westhuizen ET, Halls ML, Samuel CS, Bathgate RA, Unemori EN, Sutton SW, Summers RJ
  Title
Relaxin family peptide receptors--from orphans to therapeutic targets.
  Journal
Drug Discov Today 13:640-51 (2008)
DOI:10.1016/j.drudis.2008.04.002
Reference
PMID:17293890
  Authors
Halls ML, van der Westhuizen ET, Bathgate RA, Summers RJ
  Title
Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways.
  Journal
Br J Pharmacol 150:677-91 (2007)
DOI:10.1038/sj.bjp.0707140
Reference
PMID:16507880
  Authors
Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ
  Title
International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides.
  Journal
Pharmacol Rev 58:7-31 (2006)
DOI:10.1124/pr.58.1.9
Reference
PMID:19935741
  Authors
Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ
  Title
Cardiovascular effects of relaxin: from basic science to clinical therapy.
  Journal
Nat Rev Cardiol 7:48-58 (2010)
DOI:10.1038/nrcardio.2009.198
Reference
PMID:12646076
  Authors
Nistri S, Bani D
  Title
Relaxin receptors and nitric oxide synthases: search for the missing link.
  Journal
Reprod Biol Endocrinol 1:5 (2003)
DOI:10.1186/1477-7827-1-5
Reference
PMID:17458501
  Authors
Samuel CS, Hewitson TD, Unemori EN, Tang ML
  Title
Drugs of the future: the hormone relaxin.
  Journal
Cell Mol Life Sci 64:1539-57 (2007)
DOI:10.1007/s00018-007-6543-y
Reference
PMID:23883673
  Authors
Sasser JM
  Title
The emerging role of relaxin as a novel therapeutic pathway in the treatment of chronic kidney disease.
  Journal
Am J Physiol Regul Integr Comp Physiol 305:R559-65 (2013)
DOI:10.1152/ajpregu.00528.2012
Reference
PMID:27239943
  Authors
Sarwar M, Du XJ, Dschietzig TB, Summers RJ
  Title
The actions of relaxin on the human cardiovascular system.
  Journal
Br J Pharmacol 174:933-949 (2017)
DOI:10.1111/bph.13523
Reference
PMID:15956688
  Authors
Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ
  Title
Receptors for relaxin family peptides.
  Journal
Ann N Y Acad Sci 1041:61-76 (2005)
DOI:10.1196/annals.1282.010
Reference
PMID:22936987
  Authors
Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD, Samuel CS
  Title
Relaxin signals through a RXFP1-pERK-nNOS-NO-cGMP-dependent pathway to up-regulate matrix metalloproteinases: the additional involvement of iNOS.
  Journal
PLoS One 7:e42714 (2012)
DOI:10.1371/journal.pone.0042714
Reference
PMID:16814863
  Authors
Samuel CS, Du XJ, Bathgate RA, Summers RJ
  Title
'Relaxin' the stiffened heart and arteries: the therapeutic potential for relaxin in the treatment of cardiovascular disease.
  Journal
Pharmacol Ther 112:529-52 (2006)
DOI:10.1016/j.pharmthera.2005.05.012
Reference
PMID:25759289
  Authors
Wilson SS, Ayaz SI, Levy PD
  Title
Relaxin: a novel agent for the treatment of acute heart failure.
  Journal
Pharmacotherapy 35:315-27 (2015)
DOI:10.1002/phar.1548
Reference
PMID:16569707
  Authors
Halls ML, Bathgate RA, Summers RJ
  Title
Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms.
  Journal
Mol Pharmacol 70:214-26 (2006)
DOI:10.1124/mol.105.021691
Reference
PMID:26294284
  Authors
Kocan M, Ang SY, Summers RJ
  Title
Orthosteric, Allosteric and Biased Signalling at the Relaxin-3 Receptor RXFP3.
  Journal
Neurochem Res 41:610-9 (2016)
DOI:10.1007/s11064-015-1701-3
Reference
PMID:17351017
  Authors
van der Westhuizen ET, Werry TD, Sexton PM, Summers RJ
  Title
The relaxin family peptide receptor 3 activates extracellular signal-regulated kinase 1/2 through a protein kinase C-dependent mechanism.
  Journal
Mol Pharmacol 71:1618-29 (2007)
DOI:10.1124/mol.106.032763
Related
pathway
oaa04010  MAPK signaling pathway
oaa04020  Calcium signaling pathway
oaa04024  cAMP signaling pathway
oaa04064  NF-kappa B signaling pathway
oaa04151  PI3K-Akt signaling pathway
oaa04270  Vascular smooth muscle contraction
oaa04350  TGF-beta signaling pathway
oaa04370  VEGF signaling pathway
KO pathway
ko04926   
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