KEGG   PATHWAY: sbq04926
Entry
sbq04926                    Pathway                                
Name
Relaxin signaling pathway - Saimiri boliviensis boliviensis (Bolivian squirrel monkey)
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
sbq04926  Relaxin signaling pathway
sbq04926

Organism
Saimiri boliviensis boliviensis (Bolivian squirrel monkey) [GN:sbq]
Gene
101032411  RLN1; prorelaxin H1 [KO:K21998]
101027969  RXFP1; LOW QUALITY PROTEIN: relaxin receptor 1 [KO:K04306]
101049046  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
101042629  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101041681  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
101032105  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101043452  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
104652116  neuroendocrine secretory protein 55 [KO:K04632]
101041488  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
101050677  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
101030203  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
101030409  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
101038619  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
101041345  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
101030348  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
101037908  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
101030524  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
101044875  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
101051683  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
101046368  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
101044114  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
101049747  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
101034152  cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
101036705  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101043989  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma isoform X1 [KO:K04345] [EC:2.7.11.11]
101047300  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101034085  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101035834  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101034435  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101042795  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
101044974  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101036473  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
101052885  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101041199  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X4 [KO:K09048]
101054090  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
101047355  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
101032691  VEGFA; vascular endothelial growth factor A isoform X1 [KO:K05448]
101028762  VEGFB; vascular endothelial growth factor B [KO:K16858]
101044650  FIGF; vascular endothelial growth factor D isoform X1 [KO:K05449]
101048128  VEGFC; vascular endothelial growth factor C [KO:K05449]
101048714  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
101035787  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101035406  RELA; transcription factor p65 [KO:K04735]
101041016  NOS2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
101029768  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101052779  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101027982  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101032496  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101033359  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101050592  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101039978  PRKCZ; protein kinase C zeta type isoform X4 [KO:K18952] [EC:2.7.11.13]
101054052  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
101040361  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101036151  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101038546  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101043202  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101042210  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
101036569  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
101034861  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101045714  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101040766  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101034220  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
101034544  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
101052988  EDN1; endothelin-1 isoform X2 [KO:K16366]
101052365  EDNRB; endothelin B receptor [KO:K04198]
101051246  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
101050615  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
101047980  TGFB1; transforming growth factor beta-1 isoform X2 [KO:K13375]
101030583  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
101034142  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
101040653  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
101035102  ACTA2; actin, aortic smooth muscle [KO:K12313]
101051510  COL1A1; collagen alpha-1(I) chain isoform X1 [KO:K06236]
101045518  COL1A2; collagen alpha-2(I) chain [KO:K06236]
101039232  COL3A1; collagen alpha-1(III) chain [KO:K19720]
101035708  COL4A5; collagen alpha-5(IV) chain isoform X3 [KO:K06237]
101051846  COL4A6; collagen alpha-6(IV) chain [KO:K06237]
101038957  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
101034927  COL4A3; collagen alpha-3(IV) chain isoform X1 [KO:K06237]
101035241  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
101044518  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
101034392  INSL3; insulin-like 3 [KO:K21999]
101028092  RXFP2; relaxin receptor 2 [KO:K04307]
101037680  RLN3; relaxin-3 [KO:K22000]
101049198  RXFP3; relaxin-3 receptor 1 [KO:K08397]
101027981  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
101043334  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101040601  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101044688  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
101037803  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
101032672  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
101034552  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
101052034  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
101046851  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
101047168  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858] [EC:3.1.4.11]
101052271  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
101029401  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101046010  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
101037589  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
101047840  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
101037444  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101044137  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
101040899  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
101052690  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
101039160  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101027742  MAPK9; mitogen-activated protein kinase 9 isoform X4 [KO:K04440] [EC:2.7.11.24]
101048066  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101043809  JUN; transcription factor AP-1 [KO:K04448]
101046701  FOS; proto-oncogene c-Fos [KO:K04379]
101047663  HRAS; GTPase HRas isoform X2 [KO:K02833]
101047035  KRAS; GTPase KRas isoform X1 [KO:K07827]
101036877  NRAS; GTPase NRas [KO:K07828]
101051959  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
101038895  SHC1; SHC-transforming protein 1 [KO:K06279]
101047748  SHC-transforming protein 1 [KO:K06279]
101048523  SHC2; SHC-transforming protein 2 [KO:K17447]
101028764  SHC3; SHC-transforming protein 3 [KO:K17448]
101032627  SHC4; SHC-transforming protein 4 [KO:K17449]
101036943  SOS1; son of sevenless homolog 1 [KO:K03099]
101046427  SOS2; son of sevenless homolog 2 [KO:K03099]
101037722  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
101046584  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
101047461  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
101038666  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
101051440  INSL5; insulin-like peptide INSL5 [KO:K22001]
101051651  RXFP4; LOW QUALITY PROTEIN: relaxin-3 receptor 2 [KO:K08398]
101030896  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
sbq04010  MAPK signaling pathway
sbq04020  Calcium signaling pathway
sbq04024  cAMP signaling pathway
sbq04064  NF-kappa B signaling pathway
sbq04151  PI3K-Akt signaling pathway
sbq04270  Vascular smooth muscle contraction
sbq04350  TGF-beta signaling pathway
sbq04370  VEGF signaling pathway
KO pathway
ko04926   
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