KEGG   PATHWAY: sara04926
Entry
sara04926                   Pathway                                
Name
Relaxin signaling pathway - Sorex araneus (European shrew)
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
sara04926  Relaxin signaling pathway
sara04926

Organism
Sorex araneus (European shrew) [GN:sara]
Gene
101540073  prorelaxin-like [KO:K21998]
101540338  prorelaxin-like [KO:K21998]
101539239  RXFP1; relaxin receptor 1 [KO:K04306]
101555708  guanine nucleotide-binding protein G(o) subunit alpha [KO:K04534]
101546592  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X3 [KO:K04534]
101544375  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101538556  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101545200  guanine nucleotide-binding protein G(i) subunit alpha-like [KO:K04630]
101545636  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101539470  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
101542668  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform X1 [KO:K04536]
101556740  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
101547419  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
101556046  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
101542101  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
101537346  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
101539394  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
101558836  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
101548469  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
101558565  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
101551819  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101539926  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101555578  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101546696  cAMP-dependent protein kinase catalytic subunit-like [KO:K04345] [EC:2.7.11.11]
101554719  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
101552417  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101539734  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101539159  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101554214  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101538215  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
101543170  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101542980  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101553377  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
101554016  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
101551180  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
101548477  VEGFA; vascular endothelial growth factor A isoform X3 [KO:K05448]
101549227  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
101539272  VEGFC; vascular endothelial growth factor C [KO:K05449]
101552026  FIGF; vascular endothelial growth factor D [KO:K05449]
101556810  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
101549580  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
101543163  RELA; transcription factor p65 [KO:K04735]
101548820  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
101542917  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101556597  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101548304  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
101547106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101541868  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101540938  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101557147  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
101545329  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101550720  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101555057  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101559341  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101541587  mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
101545848  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101540694  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
101545527  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
101543096  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101559009  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101543371  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101547011  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
101559239  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
101538407  EDN1; endothelin-1 [KO:K16366]
101538515  EDNRB; endothelin B receptor [KO:K04198]
101545391  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
101544591  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
101551346  TGFB1; transforming growth factor beta-1 [KO:K13375]
101537676  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
101553495  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
101547889  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
101556706  ACTA2; actin, aortic smooth muscle isoform X1 [KO:K12313]
101547414  COL1A1; collagen alpha-1(I) chain [KO:K06236]
101537258  COL1A2; collagen alpha-2(I) chain [KO:K06236]
101551617  COL3A1; collagen alpha-1(III) chain [KO:K19720]
101551980  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
101543392  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
101540808  COL4A5; collagen alpha-5(IV) chain [KO:K06237]
101541335  COL4A6; collagen alpha-6(IV) chain [KO:K06237]
101552244  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
101543125  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
101553720  INSL3; insulin-like 3 [KO:K21999]
101541857  RXFP2; relaxin receptor 2 [KO:K04307]
101540502  RLN3; relaxin-3 [KO:K22000]
101547487  RXFP3; relaxin-3 receptor 1 [KO:K08397]
101557843  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101539413  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101547055  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101539776  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
101549131  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
101543858  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101550559  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101551730  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101551223  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
101546811  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
101547690  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101559179  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101551961  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101542924  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
101554595  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
101536977  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101537598  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
101554044  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
101545321  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
101538553  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101556557  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101556063  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101545059  FOS; proto-oncogene c-Fos isoform X1 [KO:K04379]
101546777  HRAS; GTPase HRas [KO:K02833]
101557531  KRAS; GTPase KRas isoform X1 [KO:K07827]
101559343  NRAS; GTPase NRas [KO:K07828]
101559065  SRC; proto-oncogene tyrosine-protein kinase Src isoform X2 [KO:K05704] [EC:2.7.10.2]
101553821  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
101550526  SHC2; SHC-transforming protein 2 [KO:K17447]
101550468  SHC3; SHC-transforming protein 3 [KO:K17448]
101537303  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
101550972  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
101555769  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101548295  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
101538489  ARRB1; beta-arrestin-1 [KO:K04439]
101552863  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
101544020  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
101545077  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
sara04010  MAPK signaling pathway
sara04020  Calcium signaling pathway
sara04024  cAMP signaling pathway
sara04064  NF-kappa B signaling pathway
sara04151  PI3K-Akt signaling pathway
sara04270  Vascular smooth muscle contraction
sara04350  TGF-beta signaling pathway
sara04370  VEGF signaling pathway
KO pathway
ko04926   
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