KEGG   PATHWAY: rbb04926
Entry
rbb04926                    Pathway                                
Name
Relaxin signaling pathway - Rhinopithecus bieti (black snub-nosed monkey)
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
rbb04926  Relaxin signaling pathway
rbb04926

Organism
Rhinopithecus bieti (black snub-nosed monkey) [GN:rbb]
Gene
108527806  RLN2; prorelaxin H2 [KO:K21998]
108520371  RXFP1; relaxin receptor 1 [KO:K04306]
108519632  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
108534866  GNAI1; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
108526962  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
108541624  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
108541626  neuroendocrine secretory protein 55 [KO:K04632]
108536033  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
108538195  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
108542034  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
108532909  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
108538179  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
108513682  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X1 [KO:K07826]
108533573  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
108522231  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
108515100  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
108527696  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
108531452  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
108531050  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
108521438  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
108517188  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
108532869  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
108519469  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
108517177  guanine nucleotide-binding protein G(T) subunit gamma-T1-like [KO:K04548]
108516491  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
108517430  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
108514761  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
108540003  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
108527683  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
108530264  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
108540349  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
108527163  ATF2; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
108520463  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
108519245  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
108518996  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
108542557  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
108512141  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
108518846  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
108535460  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
108519898  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
108533452  VEGFA; vascular endothelial growth factor A isoform X1 [KO:K05448]
108542677  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
108539697  VEGFD; vascular endothelial growth factor D [KO:K05449]
108534048  VEGFC; vascular endothelial growth factor C [KO:K05449]
108519636  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
108532817  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
108543519  RELA; transcription factor p65 [KO:K04735]
108539959  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
108544591  PIK3CB; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
108532960  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
108539355  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
108535636  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
108534276  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
108541175  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
108536030  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
108517986  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
108514672  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
108512087  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
108523695  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
108536070  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
108531264  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
108533326  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
108512498  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
108539069  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
108521880  AKT1; LOW QUALITY PROTEIN: RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
108532525  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
108539288  NOS1; LOW QUALITY PROTEIN: nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
108541613  EDN1; endothelin-1 [KO:K16366]
108529118  EDNRB; endothelin B receptor [KO:K04198]
108514074  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
108514066  MMP13; collagenase 3 isoform X1 [KO:K07994] [EC:3.4.24.-]
108536158  TGFB1; transforming growth factor beta-1 isoform X1 [KO:K13375]
108512466  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
108516558  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
108519603  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
108526651  ACTA2; actin, aortic smooth muscle [KO:K12313]
108516437  COL1A1; collagen alpha-1(I) chain [KO:K06236]
108517180  COL1A2; LOW QUALITY PROTEIN: collagen alpha-2(I) chain [KO:K06236]
108524396  COL3A1; LOW QUALITY PROTEIN: collagen alpha-1(III) chain [KO:K19720]
108527057  COL4A1; LOW QUALITY PROTEIN: collagen alpha-1(IV) chain [KO:K06237]
108527058  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
108522717  collagen alpha-6(IV) chain-like [KO:K06237]
108538728  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
108538749  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
108534231  INSL3; LOW QUALITY PROTEIN: insulin-like 3 [KO:K21999]
108524799  RXFP2; LOW QUALITY PROTEIN: relaxin receptor 2 [KO:K04307]
108514782  RLN3; relaxin-3 [KO:K22000]
108528721  RXFP3; relaxin-3 receptor 1 [KO:K08397]
108534793  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
108536960  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
108543021  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
108540946  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
108543933  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
108522948  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
108514094  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
108538326  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
108526885  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
108542252  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
108527553  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
108527564  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
108517746  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
108517313  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
108534524  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
108528326  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
108528327  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
108539403  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
108539422  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
108537794  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
108521141  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
108517508  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
108532921  JUN; transcription factor AP-1 [KO:K04448]
108534930  FOS; proto-oncogene c-Fos [KO:K04379]
108543525  HRAS; GTPase HRas isoform X1 [KO:K02833]
108523748  KRAS; GTPase KRas isoform X1 [KO:K07827]
108528122  NRAS; GTPase NRas [KO:K07828]
108519844  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
108526812  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
108533994  SHC-transforming protein 2-like [KO:K17447]
108531776  SHC2; SHC-transforming protein 2 [KO:K17447]
108532239  SHC3; SHC-transforming protein 3 [KO:K17448]
108530104  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
108513636  SOS2; son of sevenless homolog 2 [KO:K03099]
108520869  SOS1; son of sevenless homolog 1 [KO:K03099]
108537632  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
108520727  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
108522039  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
108537414  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
108532962  INSL5; insulin-like peptide INSL5 [KO:K22001]
108515539  RXFP4; relaxin-3 receptor 2 [KO:K08398]
108512682  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
rbb04010  MAPK signaling pathway
rbb04020  Calcium signaling pathway
rbb04024  cAMP signaling pathway
rbb04064  NF-kappa B signaling pathway
rbb04151  PI3K-Akt signaling pathway
rbb04270  Vascular smooth muscle contraction
rbb04350  TGF-beta signaling pathway
rbb04370  VEGF signaling pathway
KO pathway
ko04926   
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