KEGG   PATHWAY: pvp04926
Entry
pvp04926                    Pathway                                
Name
Relaxin signaling pathway - Pteropus vampyrus (large flying fox)
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
pvp04926  Relaxin signaling pathway
pvp04926

Organism
Pteropus vampyrus (large flying fox) [GN:pvp]
Gene
105303173  RLN2; prorelaxin H2 [KO:K21998]
105294498  RXFP1; LOW QUALITY PROTEIN: relaxin receptor 1 [KO:K04306]
105292074  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
105297202  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105295155  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105295517  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105296083  neuroendocrine secretory protein 55-like [KO:K04632]
105303584  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105299738  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
105295952  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
105307521  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
105288758  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105309385  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
105297807  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X2 [KO:K04540]
105302718  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 isoform X1 [KO:K04541]
105289068  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
105310269  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
111744611  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
105307968  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105294373  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
105307158  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
105295886  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
105303281  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X4 [KO:K04547]
105294383  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
105307274  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
105288850  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105289063  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105308501  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
105298404  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
105290195  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
105298070  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
105296460  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
105306745  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
105290070  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
105306466  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
105291624  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
105293217  cyclic AMP-responsive element-binding protein 5 [KO:K09047]
105305286  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
105288488  VEGFA; vascular endothelial growth factor A isoform X1 [KO:K05448]
105297988  VEGFB; vascular endothelial growth factor B [KO:K16858]
105299636  VEGFC; vascular endothelial growth factor C [KO:K05449]
105293998  VEGFD; vascular endothelial growth factor D [KO:K05449]
105303182  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
105293029  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105297999  RELA; transcription factor p65 [KO:K04735]
105291934  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
105307215  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105307575  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105308956  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
105296605  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105297140  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105299371  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
105303610  PRKCZ; LOW QUALITY PROTEIN: protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
105299021  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105309827  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
105306744  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105289326  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
105304566  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
105292047  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
105298192  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
105303899  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105300159  RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
105298702  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105303769  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
105289401  NOS1; LOW QUALITY PROTEIN: nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
105293961  EDN1; endothelin-1 [KO:K16366]
105288995  endothelin receptor type B [KO:K04198]
105297437  interstitial collagenase [KO:K01388] [EC:3.4.24.7]
105297439  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
105307945  TGFB1; transforming growth factor beta-1 [KO:K13375]
105296245  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
105292451  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
105292640  SMAD2; mothers against decapentaplegic homolog 2 isoform X3 [KO:K04500]
105293137  ACTA2; actin, aortic smooth muscle [KO:K12313]
105294361  COL1A2; collagen alpha-2(I) chain [KO:K06236]
105295430  COL1A1; collagen alpha-1(I) chain [KO:K06236]
105289568  COL3A1; collagen alpha-1(III) chain [KO:K19720]
105294766  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
105296151  COL4A6; collagen alpha-6(IV) chain [KO:K06237]
105301331  COL4A2; collagen alpha-2(IV) chain isoform X1 [KO:K06237]
105294764  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
105301330  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
105296119  collagen alpha-5(IV) chain isoform X1 [KO:K06237]
105296613  INSL3; insulin-like 3 [KO:K21999]
105306580  RXFP2; LOW QUALITY PROTEIN: relaxin receptor 2 [KO:K04307]
105308515  RLN3; relaxin-3 [KO:K22000]
105289721  RXFP3; relaxin-3 receptor 1 [KO:K08397]
105308299  adenylate cyclase type 1-like [KO:K08041] [EC:4.6.1.1]
105299581  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
105289813  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
105309400  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
105297518  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
105292087  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
105301250  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
105303095  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
105297846  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
105288781  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
105298737  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
105299444  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
105297702  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105291271  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X4 [KO:K04430] [EC:2.7.12.2]
105307700  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
105308283  mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
105301035  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
105301036  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
105288933  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105289628  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
105299978  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105303436  JUN; transcription factor AP-1 [KO:K04448]
105299213  FOS; proto-oncogene c-Fos [KO:K04379]
105305933  HRAS; GTPase HRas isoform X1 [KO:K02833]
105294059  KRAS; GTPase KRas isoform X2 [KO:K07827]
105296550  NRAS; GTPase NRas isoform X1 [KO:K07828]
105296513  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
105296379  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
105302278  SHC2; SHC-transforming protein 2 [KO:K17447]
105300265  SHC3; SHC-transforming protein 3 [KO:K17448]
105288811  SHC4; SHC-transforming protein 4 [KO:K17449]
105292949  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
105309535  SOS2; son of sevenless homolog 2 [KO:K03099]
105297636  ARRB1; beta-arrestin-1 isoform X2 [KO:K04439]
105291748  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
105306141  epidermal growth factor receptor-like [KO:K04361] [EC:2.7.10.1]
105293353  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
105298369  INSL5; insulin-like peptide INSL5 [KO:K22001]
105296353  RXFP4; relaxin-3 receptor 2 [KO:K08398]
105300437  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
pvp04010  MAPK signaling pathway
pvp04020  Calcium signaling pathway
pvp04024  cAMP signaling pathway
pvp04064  NF-kappa B signaling pathway
pvp04151  PI3K-Akt signaling pathway
pvp04270  Vascular smooth muscle contraction
pvp04350  TGF-beta signaling pathway
pvp04370  VEGF signaling pathway
KO pathway
ko04926   
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