KEGG   PATHWAY: cjc04926Help
Entry
cjc04926                    Pathway                                

Name
Relaxin signaling pathway - Callithrix jacchus (white-tufted-ear marmoset)
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
BRITE hierarchy
Pathway map
cjc04926  Relaxin signaling pathway
cjc04926

Ortholog table
Organism
Callithrix jacchus (white-tufted-ear marmoset) [GN:cjc]
Gene
100414702  RLN2; relaxin 2 [KO:K21998]
100390336  RXFP1; relaxin/insulin like family peptide receptor 1 [KO:K04306]
100389396  GNAO1; G protein subunit alpha o1 [KO:K04534]
103789429  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha-like [KO:K04534]
100404474  GNAI2; G protein subunit alpha i2 [KO:K04630]
100405745  GNAI3; G protein subunit alpha i3 [KO:K04630]
100388113  GNAI1; G protein subunit alpha i1 [KO:K04630]
100408515  GNAS; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
100412968  GNB1; G protein subunit beta 1 [KO:K04536]
100395033  GNB2; G protein subunit beta 2 [KO:K04537]
100407336  GNB3; G protein subunit beta 3 [KO:K07825]
100395633  GNB4; G protein subunit beta 4 [KO:K04538]
100415506  GNB5; G protein subunit beta 5 [KO:K04539]
100391372  GNG2; G protein subunit gamma 2 [KO:K07826]
100397915  GNG3; G protein subunit gamma 3 [KO:K04540]
100411028  GNG4; G protein subunit gamma 4 [KO:K04541]
103787193  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
100411155  GNG7; G protein subunit gamma 7 [KO:K04543]
100385281  GNG10; G protein subunit gamma 10 [KO:K04545]
100412160  GNG11; G protein subunit gamma 11 [KO:K04546]
100396640  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
100394978  GNG12; G protein subunit gamma 12 [KO:K04347]
108594009  GNG13; G protein subunit gamma 13 [KO:K04547]
100412503  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
100394732  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
100412782  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
100392123  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
100407753  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100408115  cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
100407692  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
100400737  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100407681  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
100414156  ATF2; activating transcription factor 2 [KO:K04450]
100392193  ATF4; activating transcription factor 4 [KO:K04374]
100394351  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
100408954  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
100406635  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
100411140  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
100409637  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
100392579  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
100411862  ATF6B; activating transcription factor 6 beta [KO:K09049]
100389629  VEGFA; vascular endothelial growth factor A [KO:K05448]
100400081  VEGFB; vascular endothelial growth factor B [KO:K16858]
100395294  VEGFC; vascular endothelial growth factor C [KO:K05449]
100407908  VEGFD; vascular endothelial growth factor D [KO:K05449]
100402266  NFKBIA; NFKB inhibitor alpha [KO:K04734]
100415321  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
100388493  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
100403192  NOS2; nitric oxide synthase 2 [KO:K13241] [EC:1.14.13.39]
100403494  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
100391655  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
100398849  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
100406689  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
100392639  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
100414659  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
100394749  PRKCZ; protein kinase C zeta [KO:K18952] [EC:2.7.11.13]
100415300  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
100387394  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100393991  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100400700  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100404815  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100387448  MMP2; matrix metallopeptidase 2 [KO:K01398] [EC:3.4.24.24]
100415095  MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:3.4.24.35]
100404447  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
100399039  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
100388080  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
100405019  NOS3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
100895717  NOS1; nitric oxide synthase 1 [KO:K13240] [EC:1.14.13.39]
100414848  EDN1; endothelin 1 [KO:K16366]
100412645  EDNRB; endothelin receptor type B [KO:K04198]
100400727  MMP1; matrix metallopeptidase 1 [KO:K01388] [EC:3.4.24.7]
100396943  MMP13; matrix metallopeptidase 13 [KO:K07994] [EC:3.4.24.-]
100401979  TGFB1; transforming growth factor beta 1 [KO:K13375]
100389596  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
100404359  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
100396826  SMAD2; SMAD family member 2 [KO:K04500]
100396597  ACTA2; actin, alpha 2, smooth muscle, aorta [KO:K12313]
100411438  COL1A2; collagen type I alpha 2 chain [KO:K06236]
100386176  COL1A1; collagen type I alpha 1 chain [KO:K06236]
100394494  COL3A1; collagen type III alpha 1 chain [KO:K19720]
100405184  COL4A2; collagen type IV alpha 2 chain [KO:K06237]
100400812  COL4A1; collagen type IV alpha 1 chain [KO:K06237]
100388823  COL4A3; collagen type IV alpha 3 chain [KO:K06237]
100388461  COL4A4; collagen type IV alpha 4 chain [KO:K06237]
100394953  COL4A6; collagen type IV alpha 6 chain [KO:K06237]
100409842  COL4A5; collagen type IV alpha 5 chain [KO:K06237]
100404744  INSL3; insulin like 3 [KO:K21999]
100396176  RXFP2; relaxin/insulin like family peptide receptor 2 [KO:K04307]
100394939  RLN3; relaxin 3 [KO:K22000]
100406423  RXFP3; relaxin/insulin like family peptide receptor 3 [KO:K08397]
100394265  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
100385658  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
100415165  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
100415141  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
100406617  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
100404620  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
100404484  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
100405403  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
100386921  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
100400803  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
100409716  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
100410075  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
100391814  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
100386168  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
100412930  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
100396611  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
100396967  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100404377  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
100405093  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100392721  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
100387686  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
100390109  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
100400411  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
100390054  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
100406017  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
100414782  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
100386165  SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
100390337  SHC1; SHC adaptor protein 1 [KO:K06279]
100415083  SHC2; SHC adaptor protein 2 [KO:K17447]
100402406  SHC3; SHC adaptor protein 3 [KO:K17448]
100392220  SHC4; SHC adaptor protein 4 [KO:K17449]
100414931  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
100410124  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
100385378  ARRB1; arrestin beta 1 [KO:K04439]
100387113  ARRB2; arrestin beta 2 [KO:K04439]
100412158  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
100395682  GRB2; growth factor receptor bound protein 2 [KO:K04364]
100391358  INSL5; insulin like 5 [KO:K22001]
100396370  RXFP4; relaxin/insulin like family peptide receptor 4 [KO:K08398]
100387454  GNA15; G 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
  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
  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
  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
  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
  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
  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
  Authors
Nistri S, Bani D
  Title
Relaxin receptors and nitric oxide synthases: search for the missing link.
  Journal
Reprod Biol Endocrinol 1:5 (2003)
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
KO pathway
ko04926   

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