KEGG   PATHWAY: pps04926
Entry
pps04926                    Pathway                                
Name
Relaxin signaling pathway - Pan paniscus (bonobo)
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
pps04926  Relaxin signaling pathway
pps04926

Organism
Pan paniscus (bonobo) [GN:pps]
Gene
100982014  prorelaxin H2 isoform X1 [KO:K21998]
100982570  prorelaxin H1 isoform X1 [KO:K21998]
100976034  RXFP1; relaxin receptor 1 isoform X4 [KO:K04306]
100991540  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X2 [KO:K04534]
100968961  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
100974334  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
100985590  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X2 [KO:K04630]
100990650  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
117974231  neuroendocrine secretory protein 55 [KO:K04632]
100978523  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100982509  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100968267  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
100967770  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100990010  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100970547  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100995028  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
100980807  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100973322  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
117975026  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
100983091  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
100987458  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 isoform X1 [KO:K04544]
112437196  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100978647  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100976735  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100992242  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 isoform X2 [KO:K04347]
112437428  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100977074  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 isoform X2 [KO:K04548]
100994102  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100989177  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
100982589  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
100970917  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X5 [KO:K04345] [EC:2.7.11.11]
100968237  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100974672  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X2 [KO:K05870]
100985706  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100980724  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
100988487  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100986194  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100981063  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100977804  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100989680  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100977358  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100973232  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
100993334  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100970217  VEGFA; vascular endothelial growth factor A isoform X5 [KO:K05448]
117974938  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
100969999  VEGFD; vascular endothelial growth factor D [KO:K05449]
100990660  VEGFC; vascular endothelial growth factor C [KO:K05449]
100972867  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100979341  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X3 [KO:K02580]
100988429  RELA; transcription factor p65 isoform X1 [KO:K04735]
100976546  NOS2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
100989732  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100990828  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100990108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100994315  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100986080  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
100969981  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100987713  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100972902  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100988422  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100977025  dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
100988437  dual specificity mitogen-activated protein kinase kinase 2-like [KO:K04369] [EC:2.7.12.2]
100979542  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
100995567  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100970966  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
100974722  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
100969444  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100991804  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100969217  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100974638  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
100996089  NOS1; nitric oxide synthase, brain isoform X1 [KO:K13240] [EC:1.14.13.39]
100982777  EDN1; endothelin-1 isoform X1 [KO:K16366]
100986370  EDNRB; endothelin receptor type B [KO:K04198]
100995251  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
100994591  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
100980947  TGFB1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
100984463  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100985497  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
100980706  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100987623  ACTA2; actin, aortic smooth muscle [KO:K12313]
100974826  COL1A2; collagen alpha-2(I) chain [KO:K06236]
100991060  COL1A1; collagen alpha-1(I) chain [KO:K06236]
100992008  COL3A1; collagen alpha-1(III) chain [KO:K19720]
100983653  COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237]
100984686  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
100972511  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
100972868  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
100976901  COL4A1; collagen alpha-1(IV) chain isoform X1 [KO:K06237]
100977235  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
100974834  RXFP2; relaxin receptor 2 isoform X1 [KO:K04307]
100988811  RXFP3; relaxin-3 receptor 1 [KO:K08397]
100984585  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
100992014  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100995134  ADCY3; adenylate cyclase type 3 isoform X4 [KO:K08043] [EC:4.6.1.1]
100978200  ADCY4; adenylate cyclase type 4 isoform X3 [KO:K08044] [EC:4.6.1.1]
100991116  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100984225  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100994715  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100972356  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
100969660  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858] [EC:3.1.4.11]
100987524  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100969344  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X4 [KO:K05858] [EC:3.1.4.11]
100978643  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100967981  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100991495  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
100989537  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
100982544  MAPK13; mitogen-activated protein kinase 13 isoform X5 [KO:K04441] [EC:2.7.11.24]
100983649  MAPK14; mitogen-activated protein kinase 14 isoform X2 [KO:K04441] [EC:2.7.11.24]
100981268  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100980937  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
100984173  MAPK10; mitogen-activated protein kinase 10 isoform X3 [KO:K04440] [EC:2.7.11.24]
100982480  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100990080  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100980908  JUN; transcription factor AP-1 [KO:K04448]
100987957  FOS; proto-oncogene c-Fos [KO:K04379]
100993386  HRAS; GTPase HRas isoform X1 [KO:K02833]
100990801  KRAS; GTPase KRas isoform X1 [KO:K07827]
100970465  NRAS; GTPase NRas isoform X2 [KO:K07828]
100986423  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
100993361  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
100974798  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
100972624  SHC3; SHC-transforming protein 3 isoform X2 [KO:K17448]
100991042  SHC4; SHC-transforming protein 4 [KO:K17449]
100972953  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100980038  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100988967  ARRB2; beta-arrestin-2 isoform X2 [KO:K04439]
100984768  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
100974885  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100993451  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100979070  INSL5; insulin-like peptide INSL5 [KO:K22001]
100985577  RXFP4; relaxin-3 receptor 2 [KO:K08398]
100987012  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
pps04010  MAPK signaling pathway
pps04020  Calcium signaling pathway
pps04024  cAMP signaling pathway
pps04064  NF-kappa B signaling pathway
pps04151  PI3K-Akt signaling pathway
pps04270  Vascular smooth muscle contraction
pps04350  TGF-beta signaling pathway
pps04370  VEGF signaling pathway
KO pathway
ko04926   
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