KEGG   PATHWAY: npo04926
Entry
npo04926                    Pathway                                
Name
Relaxin signaling pathway - Nyctereutes procyonoides (raccoon dog)
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
npo04926  Relaxin signaling pathway
npo04926

Organism
Nyctereutes procyonoides (raccoon dog) [GN:npo]
Gene
129500613  prorelaxin [KO:K21998]
129516946  RXFP1; relaxin receptor 1 [KO:K04306]
129513852  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
129494269  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
129519569  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
129522106  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
129497792  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
129497848  neuroendocrine secretory protein 55 [KO:K04632]
129512833  guanine nucleotide-binding protein G(s) subunit alpha-like isoform X1 [KO:K04632]
129497735  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
129520313  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
129503454  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
129498348  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
129506463  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
129496421  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
129501173  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
129499161  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 isoform X1 [KO:K04541]
129520219  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
129520847  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
129522362  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
129499702  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
129494664  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
129498223  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
129519244  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
129521436  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
129519415  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
129498294  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
129512848  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
129503910  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
129519960  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
129521768  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
129522997  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
129518269  cyclic AMP-responsive element-binding protein 1-like [KO:K05870]
129498595  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
129511576  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
129508719  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
129494799  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
129503105  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
129515926  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
129522278  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
129502771  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
129513003  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
129512852  VEGFA; vascular endothelial growth factor A [KO:K05448]
129500583  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
129518657  VEGFD; vascular endothelial growth factor D [KO:K05449]
129515076  VEGFC; LOW QUALITY PROTEIN: vascular endothelial growth factor C [KO:K05449]
129499457  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
129521190  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
129503049  RELA; transcription factor p65 isoform X1 [KO:K04735]
129515870  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
129496789  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
129498637  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
129507069  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
129513452  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
129520803  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
129522073  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
129497722  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
129522592  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
129506345  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
129522322  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
129502349  mitogen-activated protein kinase 3-like [KO:K04371] [EC:2.7.11.24]
129507918  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
129519082  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
129513683  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
129496726  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
129508823  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129495892  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129499851  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
129517633  RAC-alpha serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
129514778  RAC-alpha serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
129515953  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
129508386  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
129508391  EDN1; endothelin-1 [KO:K16366]
129516513  EDNRB; endothelin receptor type B [KO:K04198]
129497337  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
129497416  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
129500810  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
129495112  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
129507207  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
129508622  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
129508126  ACTA2; actin, aortic smooth muscle [KO:K12313]
129498243  COL1A2; collagen alpha-2(I) chain [KO:K06236]
129507673  COL1A1; collagen alpha-1(I) chain [KO:K06236]
129498873  COL3A1; collagen alpha-1(III) chain [KO:K19720]
129516380  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
129516381  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
129523346  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
129523347  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
129517705  COL4A5; collagen alpha-5(IV) chain [KO:K06237]
129517794  COL4A6; LOW QUALITY PROTEIN: collagen alpha-6(IV) chain [KO:K06237]
129521471  INSL3; insulin-like 3 [KO:K21999]
129504512  RXFP2; relaxin receptor 2 [KO:K04307]
129522006  RLN3; relaxin-3 [KO:K22000]
129509745  RXFP3; relaxin-3 receptor 1 [KO:K08397]
129515724  LOW QUALITY PROTEIN: adenylate cyclase type 1-like [KO:K08041] [EC:4.6.1.1]
129516202  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
129498939  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
129510932  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
129499511  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
129517234  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
129513386  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
129502672  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
129519450  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
129496894  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
129504276  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
129497646  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
129500550  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
129494612  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
129497178  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
129521885  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
129511619  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
129511620  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
129512956  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
129512957  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
129494670  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
129501796  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
129522825  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
129497811  JUN; transcription factor Jun [KO:K04448]
129496401  FOS; protein c-Fos [KO:K04379]
129494224  HRAS; GTPase HRas isoform X1 [KO:K02833]
129505561  KRAS; GTPase KRas isoform X1 [KO:K07827]
129501466  NRAS; GTPase NRas [KO:K07828]
129494438  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
129508769  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
129522289  SHC2; SHC-transforming protein 2 [KO:K17447]
129500459  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
129506392  SHC4; SHC-transforming protein 4 [KO:K17449]
129496132  SOS2; son of sevenless homolog 2 [KO:K03099]
129510881  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
129497145  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
129506668  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
129494118  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
129511906  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
129496884  INSL5; LOW QUALITY PROTEIN: insulin-like peptide INSL5 [KO:K22001]
129522311  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
npo04010  MAPK signaling pathway
npo04020  Calcium signaling pathway
npo04024  cAMP signaling pathway
npo04064  NF-kappa B signaling pathway
npo04151  PI3K-Akt signaling pathway
npo04270  Vascular smooth muscle contraction
npo04350  TGF-beta signaling pathway
npo04370  VEGF signaling pathway
KO pathway
ko04926   
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