KEGG   PATHWAY: hai04926
Entry
hai04926                    Pathway                                
Name
Relaxin signaling pathway - Hipposideros armiger (great roundleaf bat)
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
hai04926  Relaxin signaling pathway
hai04926

Organism
Hipposideros armiger (great roundleaf bat) [GN:hai]
Gene
109384485  RLN2; prorelaxin H2 [KO:K21998]
109377665  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
109375288  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
109392892  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
109380071  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
109380072  neuroendocrine secretory protein 55 [KO:K04632]
109391171  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
109374903  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
109373669  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
109372679  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
109394673  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
109384336  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
109384198  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
109387705  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
109385438  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
109390646  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
109372215  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
109371938  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
109394259  uncharacterized LOC105372280 homolog [KO:K04347]
109385811  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
109371939  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
109380824  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
109387200  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
109385440  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
109394225  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
109388316  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
109388738  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
109392248  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
109373471  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
109393756  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
109388532  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
109390233  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
109388636  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
109381368  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
109373089  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
109382864  VEGFA; vascular endothelial growth factor A [KO:K05448]
109384216  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
109395927  VEGFD; vascular endothelial growth factor D isoform X1 [KO:K05449]
109387670  VEGFC; vascular endothelial growth factor C isoform X1 [KO:K05449]
109383860  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
109372541  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
109384322  RELA; transcription factor p65 isoform X1 [KO:K04735]
109385084  NOS2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
109381238  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
109394108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109372681  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109382484  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109395865  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
109373811  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
109391154  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
109384548  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
109385252  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109388626  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
109385803  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
109394900  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
109383663  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
109379910  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
109381083  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109385878  RAC-beta serine/threonine-protein kinase-like isoform X1 [KO:K04456] [EC:2.7.11.1]
109374859  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109385353  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109389680  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
109382238  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
109375416  EDN1; endothelin-1 [KO:K16366]
109389071  EDNRB; endothelin B receptor [KO:K04198]
109376363  interstitial collagenase-like [KO:K01388] [EC:3.4.24.7]
109376590  TGFB1; transforming growth factor beta-1 [KO:K13375]
109386421  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
109394441  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
109388212  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
109377704  ACTA2; actin, aortic smooth muscle [KO:K12313]
109380648  COL1A1; collagen alpha-1(I) chain [KO:K06236]
109371948  COL1A2; collagen alpha-2(I) chain [KO:K06236]
109372698  COL3A1; collagen alpha-1(III) chain [KO:K19720]
109396325  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
109393347  COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237]
109393353  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
109390501  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
109383936  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
109383910  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
109382411  INSL3; insulin-like 3 [KO:K21999]
109388010  RXFP2; relaxin receptor 2 [KO:K04307]
109394263  RLN3; relaxin-3 [KO:K22000]
109385490  RXFP3; relaxin-3 receptor 1 [KO:K08397]
109373011  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
109375976  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
109385186  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
109393593  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
109393238  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
109383261  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
109372359  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
109392133  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
109378976  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
109378977  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
109384329  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
109383976  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
109380289  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
109389137  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
109396087  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
109395979  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
109395980  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
109396629  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
109396630  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
109392215  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109377948  mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
109392748  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
109371251  JUN; transcription factor AP-1 [KO:K04448]
109371257  transcription factor AP-1 [KO:K04448]
109381526  FOS; proto-oncogene c-Fos [KO:K04379]
109375639  HRAS; GTPase HRas isoform X1 [KO:K02833]
109385150  GTPase HRas-like [KO:K02833]
109389264  KRAS; GTPase KRas isoform X1 [KO:K07827]
109377015  NRAS; GTPase NRas [KO:K07828]
109377191  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
109393422  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
109390676  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
109376923  SHC3; SHC-transforming protein 3 [KO:K17448]
109394486  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
109385471  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
109375221  SOS2; son of sevenless homolog 2 [KO:K03099]
109394691  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
109386336  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
109388365  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
109383688  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
109393393  relaxin-3 receptor 2-like [KO:K08398]
109393371  relaxin-3 receptor 2-like [KO:K08398]
109388646  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
hai04010  MAPK signaling pathway
hai04020  Calcium signaling pathway
hai04024  cAMP signaling pathway
hai04064  NF-kappa B signaling pathway
hai04151  PI3K-Akt signaling pathway
hai04270  Vascular smooth muscle contraction
hai04350  TGF-beta signaling pathway
hai04370  VEGF signaling pathway
KO pathway
ko04926   
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