KEGG   PATHWAY: chx04926
Entry
chx04926                    Pathway                                
Name
Relaxin signaling pathway - Capra hircus (goat)
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
chx04926  Relaxin signaling pathway
chx04926

Organism
Capra hircus (goat) [GN:chx]
Gene
102188789  RXFP1; relaxin receptor 1 [KO:K04306]
102186145  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100860765  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102185804  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
108635583  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
102188874  guanine nucleotide-binding protein G(s) subunit alpha isoforms short isoform X1 [KO:K04632]
108633189  neuroendocrine secretory protein 55 [KO:K04632]
102187070  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
102169841  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
102191178  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
102174574  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
102189312  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X2 [KO:K07826]
102184123  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
102170665  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
102190485  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
102183232  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
102189040  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
106502450  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
102186081  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
102182581  uncharacterized LOC105372280 homolog [KO:K04347]
102175543  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
102190190  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 isoform X2 [KO:K04547]
102185427  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
102190164  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
102189798  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102173379  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102168790  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102186065  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102180634  ATF2; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
102185072  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
102180221  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
102174829  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
102183745  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
102183893  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
102170199  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
102190378  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
102171671  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100860957  VEGFA; vascular endothelial growth factor A isoform 1 precursor [KO:K05448]
102189099  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
102185645  VEGFD; vascular endothelial growth factor D [KO:K05449]
102189826  VEGFC; vascular endothelial growth factor C [KO:K05449]
102169137  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
102175660  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102174096  RELA; transcription factor p65 [KO:K04735]
100860742  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
102185042  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102168391  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102177551  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102179343  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102170135  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
102188710  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102186420  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
108638619  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
102190520  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X4 [KO:K04368] [EC:2.7.12.2]
102175285  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102186040  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102188824  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102184364  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
102168469  MMP9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
100860904  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102174051  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102187521  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102185338  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
102185490  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
102175912  EDN1; endothelin-1 isoform X1 [KO:K16366]
102186699  EDNRB; endothelin B receptor [KO:K04198]
102170620  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
102170069  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
102191364  TGFB1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
102187767  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100861300  TGFBR2; LOW QUALITY PROTEIN: TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
102188455  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
102191486  ACTA2; actin, aortic smooth muscle [KO:K12313]
100860828  COL1A1; collagen alpha-1(I) chain isoform X1 [KO:K06236]
108634775  basic proline-rich protein-like [KO:K06236]
100860940  COL1A2; collagen alpha-2(I) chain [KO:K06236]
100860938  COL3A1; collagen alpha-1(III) chain [KO:K19720]
102176677  COL4A6; collagen alpha-6(IV) chain [KO:K06237]
102176947  COL4A5; collagen alpha-5(IV) chain isoform X2 [KO:K06237]
108633195  collagen alpha-6(IV) chain-like [KO:K06237]
102171347  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
102171079  COL4A1; LOW QUALITY PROTEIN: collagen alpha-1(IV) chain [KO:K06237]
102190083  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
102190364  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
100861214  INSL3; insulin-like 3 precursor [KO:K21999]
102184068  RXFP2; relaxin receptor 2 isoform X1 [KO:K04307]
102173832  RLN3; relaxin-3 [KO:K22000]
108638475  relaxin-3 receptor 1-like [KO:K08397]
102178269  RXFP3; relaxin-3 receptor 1 [KO:K08397]
102180724  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
102171922  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
102169019  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
102185469  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
102169557  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
102185858  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
102184919  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
102188104  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
102188148  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
102180505  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
102169966  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
102189653  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
102180890  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
102175799  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
102173178  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
102180926  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100860996  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
102189174  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102184510  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
102182774  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102170408  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100861087  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102185423  JUN; transcription factor AP-1 [KO:K04448]
102171520  FOS; proto-oncogene c-Fos [KO:K04379]
102186668  HRAS; GTPase HRas isoform X1 [KO:K02833]
102172519  KRAS; GTPase KRas isoform X1 [KO:K07827]
102187180  NRAS; GTPase NRas [KO:K07828]
102182890  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
102170926  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
102169956  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
102189677  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
102179773  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
102185660  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102184154  SOS2; son of sevenless homolog 2 [KO:K03099]
102189417  ARRB1; beta-arrestin-1 isoform X3 [KO:K04439]
102186433  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
102172767  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102170356  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
102178689  INSL5; insulin-like peptide INSL5 [KO:K22001]
102176185  RXFP4; relaxin-3 receptor 2 [KO:K08398]
102177052  GNA15; guanine nucleotide-binding protein subunit alpha-15 isoform X1 [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
chx04010  MAPK signaling pathway
chx04020  Calcium signaling pathway
chx04024  cAMP signaling pathway
chx04064  NF-kappa B signaling pathway
chx04151  PI3K-Akt signaling pathway
chx04270  Vascular smooth muscle contraction
chx04350  TGF-beta signaling pathway
chx04370  VEGF signaling pathway
KO pathway
ko04926   
LinkDB

DBGET integrated database retrieval system