KEGG   PATHWAY: mmyo04926
Entry
mmyo04926                   Pathway                                
Name
Relaxin signaling pathway - Myotis myotis (greater mouse-eared bat)
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
mmyo04926  Relaxin signaling pathway
mmyo04926

Organism
Myotis myotis (greater mouse-eared bat) [GN:mmyo]
Gene
118667739  prorelaxin-like [KO:K21998]
118658481  RXFP1; relaxin receptor 1 [KO:K04306]
118674453  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
118666051  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
118673502  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha isoform X1 [KO:K04630]
118668456  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
118675794  guanine nucleotide-binding protein G(i) subunit alpha-like [KO:K04630]
118662565  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
118663143  neuroendocrine secretory protein 55-like [KO:K04632]
118655599  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
118655733  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
118649724  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
118676150  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
118651993  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
118655246  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 isoform X1 [KO:K07826]
118648957  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
118678724  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
118666631  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
118673940  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
118653683  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
118661166  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
118663367  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
118675273  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
118658681  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
118652811  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
118658043  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10-like [KO:K04545]
118667187  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
118666214  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
118652667  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 isoform X1 [KO:K04347]
118677067  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
118652936  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
118666579  guanine nucleotide-binding protein G(T) subunit gamma-T1-like [KO:K04548]
118672316  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
118676734  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
118652717  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
118675444  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
118661646  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
118661230  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
118649462  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
118666845  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
118673054  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
118666355  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
118658839  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
118667339  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
118665089  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
118666077  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
118679616  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
118660010  VEGFA; vascular endothelial growth factor A [KO:K05448]
118665372  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
118651245  VEGFC; vascular endothelial growth factor C [KO:K05449]
118654158  VEGFD; vascular endothelial growth factor D isoform X1 [KO:K05449]
118677878  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
118671867  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
118665292  RELA; transcription factor p65 [KO:K04735]
118672123  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
118677590  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118668125  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118675045  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118675217  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
118656203  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118657573  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
118655597  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
118668076  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118654213  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
118657986  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
118678650  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
118656605  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
118674505  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
118663534  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
118678909  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118655031  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118674834  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118679429  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
118678505  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
118677109  EDN1; endothelin-1 isoform X1 [KO:K16366]
118651235  EDNRB; endothelin receptor type B [KO:K04198]
118664460  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
118664457  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
118674276  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
118667263  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
118668257  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
118662725  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
118669992  ACTA2; actin, aortic smooth muscle [KO:K12313]
118666213  COL1A2; collagen alpha-2(I) chain [KO:K06236]
118671908  COL1A1; collagen alpha-1(I) chain [KO:K06236]
118661598  COL3A1; collagen alpha-1(III) chain [KO:K19720]
118651398  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
118651399  COL4A1; collagen alpha-1(IV) chain [KO:K06237]
118654149  COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237]
118654373  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
118661805  COL4A4; collagen alpha-4(IV) chain isoform X1 [KO:K06237]
118661915  COL4A3; collagen alpha-3(IV) chain [KO:K06237]
118658723  INSL3; insulin-like 3 [KO:K21999]
118650546  RXFP2; relaxin receptor 2 [KO:K04307]
118652685  relaxin-3-like [KO:K22000]
118652722  relaxin-3-like [KO:K22000]
118655924  RXFP3; relaxin-3 receptor 1 [KO:K08397]
118665883  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
118656192  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
118669221  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
118678616  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
118650262  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
118674005  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
118670715  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
118656939  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
118649794  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
118663015  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
118663147  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
118665361  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
118671569  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
118672164  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
118659182  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
118660246  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
118660247  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
118657384  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
118657754  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
118652068  mitogen-activated protein kinase 9-like [KO:K04440] [EC:2.7.11.24]
118679322  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118670993  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118676104  JUN; transcription factor AP-1 [KO:K04448]
118658230  FOS; proto-oncogene c-Fos [KO:K04379]
118648965  HRAS; GTPase HRas isoform X1 [KO:K02833]
118649554  KRAS; GTPase KRas isoform X1 [KO:K07827]
118672986  NRAS; GTPase NRas [KO:K07828]
118662917  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
118669819  LOW QUALITY PROTEIN: SHC-transforming protein 1-like [KO:K06279]
118672782  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
118659254  SHC2; SHC-transforming protein 2 [KO:K17447]
118652528  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
118651538  SHC4; SHC-transforming protein 4 [KO:K17449]
118669078  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
118654741  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
118671946  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
118664634  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
118665909  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
118671153  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
118673002  RXFP4; LOW QUALITY PROTEIN: relaxin-3 receptor 2 [KO:K08398]
118658382  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
mmyo04010  MAPK signaling pathway
mmyo04020  Calcium signaling pathway
mmyo04024  cAMP signaling pathway
mmyo04064  NF-kappa B signaling pathway
mmyo04151  PI3K-Akt signaling pathway
mmyo04270  Vascular smooth muscle contraction
mmyo04350  TGF-beta signaling pathway
mmyo04370  VEGF signaling pathway
KO pathway
ko04926   
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