KEGG   PATHWAY: psiu04926
Entry
psiu04926                   Pathway                                
Name
Relaxin signaling pathway - Phocoena sinus (vaquita)
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
psiu04926  Relaxin signaling pathway
psiu04926

Organism
Phocoena sinus (vaquita) [GN:psiu]
Gene
116756005  prorelaxin [KO:K21998]
116754259  RXFP1; relaxin receptor 1 isoform X1 [KO:K04306]
116744142  guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
116761812  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
116749946  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
116759318  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
116740990  neuroendocrine secretory protein 55-like [KO:K04632]
116740988  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
116764574  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
116739605  GNB2; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
116760197  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
116753308  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
116748817  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform X1 [KO:K04539]
116748861  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X1 [KO:K07826]
116758798  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
116742043  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
116753058  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
116763781  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
116743126  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
116752047  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
116743417  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
116744006  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
116755457  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
116759883  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 isoform X1 [KO:K04546]
116756875  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
116740969  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
116759589  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
116745853  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
116753224  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
116754197  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
116751566  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
116756730  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
116756632  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
116761029  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X1 [KO:K04374]
116755320  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
116740243  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
116758621  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
116751955  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
116759300  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
116759616  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
116762930  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
116762165  VEGFA; vascular endothelial growth factor A [KO:K05448]
116758090  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
116746676  VEGFC; vascular endothelial growth factor C [KO:K05449]
116747916  VEGFD; vascular endothelial growth factor D [KO:K05449]
116749797  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
116754222  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
116758150  RELA; transcription factor p65 isoform X1 [KO:K04735]
116745263  NOS2; LOW QUALITY PROTEIN: nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
116752953  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116752990  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
116751286  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116750604  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
116742613  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
116751944  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
116752778  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
116761625  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
116747589  MAP2K1; LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
116751189  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116738910  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
116740620  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
116743436  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
116740660  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
116743673  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
116759669  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
116748950  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
116759107  NOS3; LOW QUALITY PROTEIN: nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
116738822  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
116762788  EDN1; endothelin-1 isoform X1 [KO:K16366]
116743245  EDNRB; endothelin receptor type B isoform X1 [KO:K04198]
116758693  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
116757942  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
116743550  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
116755848  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
116761798  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
116738762  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
116741751  ACTA2; actin, aortic smooth muscle isoform X1 [KO:K12313]
116759245  COL1A2; collagen alpha-2(I) chain isoform X1 [KO:K06236]
116745191  COL1A1; collagen alpha-1(I) chain isoform X1 [KO:K06236]
116757129  COL3A1; collagen alpha-1(III) chain isoform X1 [KO:K19720]
116747864  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
116748067  COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237]
116756400  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
116756805  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
116743163  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
116743164  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
116752330  INSL3; insulin-like 3 [KO:K21999]
116743112  RXFP2; LOW QUALITY PROTEIN: relaxin receptor 2 [KO:K04307]
116751886  RLN3; LOW QUALITY PROTEIN: relaxin-3 [KO:K22000]
116751119  RXFP3; LOW QUALITY PROTEIN: relaxin-3 receptor 1 [KO:K08397]
116759445  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
116752275  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
116764233  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
116749116  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
116760787  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
116744731  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
116742406  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
116740403  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
116749106  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
116740640  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
116740954  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
116758215  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
116745476  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
116745732  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
116753033  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 4-like [KO:K04430] [EC:2.7.12.2]
116750630  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
116760605  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
116760782  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
116762796  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
116762798  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
116754735  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
116741257  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
116751302  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
116761115  JUN; transcription factor AP-1 [KO:K04448]
116749519  FOS; proto-oncogene c-Fos [KO:K04379]
116757893  HRAS; GTPase HRas isoform X1 [KO:K02833]
116751649  uncharacterized protein LOC116751649 [KO:K02833]
116760326  KRAS; GTPase KRas isoform X1 [KO:K07827]
116739088  NRAS; GTPase NRas [KO:K07828]
116740153  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
116740554  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
116751918  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
116755660  SHC3; SHC-transforming protein 3 [KO:K17448]
116749591  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
116747062  SOS2; son of sevenless homolog 2 [KO:K03099]
116764289  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
116746086  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
116757726  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
116759758  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
116746378  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
116744992  INSL5; LOW QUALITY PROTEIN: insulin-like peptide INSL5 [KO:K22001]
116744579  RXFP4; LOW QUALITY PROTEIN: relaxin-3 receptor 2 [KO:K08398]
116751182  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
psiu04010  MAPK signaling pathway
psiu04020  Calcium signaling pathway
psiu04024  cAMP signaling pathway
psiu04064  NF-kappa B signaling pathway
psiu04151  PI3K-Akt signaling pathway
psiu04270  Vascular smooth muscle contraction
psiu04350  TGF-beta signaling pathway
psiu04370  VEGF signaling pathway
KO pathway
ko04926   
LinkDB

DBGET integrated database retrieval system