KEGG   PATHWAY: eju04926
Entry
eju04926                    Pathway                                
Name
Relaxin signaling pathway - Eumetopias jubatus (Steller sea lion)
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
eju04926  Relaxin signaling pathway
eju04926

Organism
Eumetopias jubatus (Steller sea lion) [GN:eju]
Gene
114219817  prorelaxin-like [KO:K21998]
114210143  RXFP1; relaxin receptor 1 [KO:K04306]
114203550  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
114225129  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
114222284  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
114207900  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
114197913  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
114197962  neuroendocrine secretory protein 55 [KO:K04632]
114213175  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
114214309  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
114222462  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
114206994  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
114206513  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
114213967  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
114220313  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
114210371  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
114208401  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
114226217  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
114197031  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
114213489  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
114220746  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
114208489  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
114197706  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
114215503  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
114220602  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 isoform X1 [KO:K04548]
114201152  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 isoform X1 [KO:K04549]
114199416  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
114208397  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
114197723  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
114215964  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
114224124  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
114218458  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
114218277  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
114226347  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
114211711  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
114198708  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
114215177  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
114221152  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
114203954  cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
114203955  cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
114222060  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
114204633  VEGFA; vascular endothelial growth factor A [KO:K05448]
114220332  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
114218047  VEGFD; vascular endothelial growth factor D [KO:K05449]
114206170  VEGFC; vascular endothelial growth factor C [KO:K05449]
114217931  NFKBIA; NF-kappa-B inhibitor alpha isoform X1 [KO:K04734]
114199341  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
114220346  RELA; transcription factor p65 [KO:K04735]
114214012  NOS2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
114213130  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
114205617  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
114206954  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
114224308  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
114224631  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
114226659  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
114213301  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
114207692  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
114206298  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
114226331  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
114202353  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
114214409  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
114204089  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
114223146  MMP9; matrix metalloproteinase-9 isoform X1 [KO:K01403] [EC:3.4.24.35]
114203265  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114203268  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114206518  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114215523  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114198019  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
114219124  NOS1; nitric oxide synthase, brain isoform X1 [KO:K13240] [EC:1.14.13.39]
114212619  EDN1; endothelin-1 [KO:K16366]
114211545  EDNRB; endothelin receptor type B [KO:K04198]
114211360  interstitial collagenase-like [KO:K01388] [EC:3.4.24.7]
114211385  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
114202548  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
114213480  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
114212271  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
114204964  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
114210273  ACTA2; actin, aortic smooth muscle [KO:K12313]
114201157  COL1A1; LOW QUALITY PROTEIN: collagen alpha-1(I) chain [KO:K06236]
114220766  COL1A2; collagen alpha-2(I) chain [KO:K06236]
114223815  COL3A1; collagen alpha-1(III) chain [KO:K19720]
114210819  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
114210852  COL4A4; collagen alpha-4(IV) chain [KO:K06237]
114196618  COL4A1; collagen alpha-1(IV) chain isoform X1 [KO:K06237]
114196641  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
114198341  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
114198363  collagen alpha-6(IV) chain-like [KO:K06237]
114226646  INSL3; insulin-like 3 [KO:K21999]
114212147  RXFP2; relaxin receptor 2 [KO:K04307]
114197687  RLN3; relaxin-3 [KO:K22000]
114204717  RXFP3; relaxin-3 receptor 1 [KO:K08397]
114213699  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
114223681  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
114205853  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
114217911  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
114225777  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
114202960  adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
114202963  adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
114211178  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
114219898  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
114216386  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
114216392  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
114220426  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
114221305  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
114196710  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
114197856  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
114200845  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
114218424  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
114218476  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
114222054  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
114222247  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
114224898  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
114201201  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
114205461  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
114212152  JUN; transcription factor AP-1 [KO:K04448]
114207358  FOS; proto-oncogene c-Fos [KO:K04379]
114201560  HRAS; GTPase HRas isoform X1 [KO:K02833]
114216565  KRAS; GTPase KRas isoform X1 [KO:K07827]
114207931  NRAS; GTPase NRas [KO:K07828]
114203512  proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
114203513  proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
114198628  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
114226321  SHC2; SHC-transforming protein 2 [KO:K17447]
114219804  SHC3; SHC-transforming protein 3 [KO:K17448]
114206514  SHC4; SHC-transforming protein 4 [KO:K17449]
114211897  SOS2; son of sevenless homolog 2 [KO:K03099]
114219700  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
114225308  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
114218593  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
114213645  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
114216301  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
114208337  INSL5; LOW QUALITY PROTEIN: insulin-like peptide INSL5 [KO:K22001]
114226230  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
eju04010  MAPK signaling pathway
eju04020  Calcium signaling pathway
eju04024  cAMP signaling pathway
eju04064  NF-kappa B signaling pathway
eju04151  PI3K-Akt signaling pathway
eju04270  Vascular smooth muscle contraction
eju04350  TGF-beta signaling pathway
eju04370  VEGF signaling pathway
KO pathway
ko04926   
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