KEGG   PATHWAY: aml04926
Entry
aml04926                    Pathway                                
Name
Relaxin signaling pathway - Ailuropoda melanoleuca (giant panda)
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
aml04926  Relaxin signaling pathway
aml04926

Organism
Ailuropoda melanoleuca (giant panda) [GN:aml]
Gene
100463775  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100464196  NRAS; GTPase NRas [KO:K07828]
100465223  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100465232  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100465448  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100465476  MAPK14; mitogen-activated protein kinase 14 isoform X3 [KO:K04441] [EC:2.7.11.24]
100465526  EDNRB; endothelin receptor type B [KO:K04198]
100465700  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100465735  VEGFB; vascular endothelial growth factor B [KO:K16858]
100465793  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100466130  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X2 [KO:K04534]
100466408  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
100466965  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100466997  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
100467069  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100467255  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100467906  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100467916  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100468080  SHC3; SHC-transforming protein 3 [KO:K17448]
100468087  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
100468197  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
100468252  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X2 [KO:K04345] [EC:2.7.11.11]
100468763  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100468916  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
100469231  [KO:K04632]
100469308  RXFP2; relaxin receptor 2 [KO:K04307]
100469628  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100469944  GNA15; guanine nucleotide-binding protein subunit alpha-15 isoform X1 [KO:K04637]
100470035  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100470060  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
100470249  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
100470496  ACTA2; actin, aortic smooth muscle [KO:K12313]
100470703  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
100470867  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100470926  EDN1; endothelin-1 [KO:K16366]
100471164  ADCY3; adenylate cyclase type 3 isoform X2 [KO:K08043] [EC:4.6.1.1]
100471622  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
100471767  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100471940  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100472104  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100472350  COL3A1; collagen alpha-1(III) chain [KO:K19720]
100472388  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100472777  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100473195  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100473680  [KO:K04632]
100473836  HRAS; GTPase HRas isoform X1 [KO:K02833]
100474121  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100474135  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X2 [KO:K04450]
100474261  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100474271  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
100474396  SOS2; son of sevenless homolog 2 isoform X9 [KO:K03099]
100474779  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100474825  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100474867  FOS; proto-oncogene c-Fos [KO:K04379]
100474885  COL1A2; collagen alpha-2(I) chain [KO:K06236]
100475137  SHC4; SHC-transforming protein 4 isoform X2 [KO:K17449]
100475291  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100475394  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
100475429  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
100475485  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
100475635  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
100475698  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
100475919  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
100475975  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
100476017  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100476111  INSL3; insulin-like 3 [KO:K21999]
100476183  MMP2; 72 kDa type IV collagenase isoform X1 [KO:K01398] [EC:3.4.24.24]
100476214  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100476237  COL1A1; collagen alpha-1(I) chain [KO:K06236]
100476284  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100476495  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100476550  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100476922  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
100476938  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
100477221  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
100477225  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 isoform X1 [KO:K04347]
100477326  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100477600  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
100477711  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100477838  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
100477951  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100478039  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100478167  MMP1; LOW QUALITY PROTEIN: interstitial collagenase [KO:K01388] [EC:3.4.24.7]
100478601  ARRB2; LOW QUALITY PROTEIN: beta-arrestin-2 [KO:K04439]
100478660  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
100478671  MMP13; collagenase 3 isoform X2 [KO:K07994] [EC:3.4.24.-]
100478752  COL4A1; collagen alpha-1(IV) chain isoform X4 [KO:K06237]
100478914  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
100479004  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
100479175  INSL5; LOW QUALITY PROTEIN: insulin-like peptide INSL5 [KO:K22001]
100479294  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100479580  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100479688  COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237]
100480040  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
100480158  RELA; transcription factor p65 isoform X1 [KO:K04735]
100480195  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
100480235  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100480414  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100480483  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
100480603  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
100480694  SHC2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
100480856  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100480861  [KO:K21998]
100481181  [KO:K01388] [EC:3.4.24.7]
100481755  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100482029  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100482196  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100482213  VEGFD; vascular endothelial growth factor D isoform X1 [KO:K05449]
100482255  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100482519  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100482526  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100482686  RLN3; relaxin-3 [KO:K22000]
100482939  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
100482983  VEGFA; vascular endothelial growth factor A [KO:K05448]
100483046  VEGFC; vascular endothelial growth factor C [KO:K05449]
100483125  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
100483209  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
100483482  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
100483514  RXFP1; relaxin receptor 1 isoform X1 [KO:K04306]
100483828  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100483834  JUN; transcription factor AP-1 [KO:K04448]
100483919  KRAS; GTPase KRas isoform X1 [KO:K07827]
100483990  NOS3; nitric oxide synthase, endothelial isoform X2 [KO:K13242] [EC:1.14.13.39]
100484531  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100484553  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100484859  RXFP3; relaxin-3 receptor 1 [KO:K08397]
100484933  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105236417  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105236905  [KO:K04545]
117800432  [KO:K01403] [EC:3.4.24.35]
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
aml04010  MAPK signaling pathway
aml04020  Calcium signaling pathway
aml04024  cAMP signaling pathway
aml04064  NF-kappa B signaling pathway
aml04151  PI3K-Akt signaling pathway
aml04270  Vascular smooth muscle contraction
aml04350  TGF-beta signaling pathway
aml04370  VEGF signaling pathway
KO pathway
ko04926   

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