KEGG   PATHWAY: mmur04926
Entry
mmur04926                   Pathway                                
Name
Relaxin signaling pathway - Microcebus murinus (gray mouse lemur)
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
mmur04926  Relaxin signaling pathway
mmur04926

Organism
Microcebus murinus (gray mouse lemur) [GN:mmur]
Gene
105856306  prorelaxin isoform X1 [KO:K21998]
105881759  RXFP1; relaxin receptor 1 isoform X1 [KO:K04306]
105866545  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
105874990  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
105864008  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
105879338  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
105874518  guanine nucleotide-binding protein G(s) subunit alpha isoforms short isoform X1 [KO:K04632]
105874520  neuroendocrine secretory protein 55-like [KO:K04632]
105877661  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
105868427  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 isoform X1 [KO:K04537]
105869000  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X2 [KO:K07825]
105855818  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
105870695  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
105867677  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
105878586  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
105856485  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
105861782  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
105873983  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
109729970  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
109731176  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
105885526  LOW QUALITY PROTEIN: uncharacterized LOC105372280 homolog [KO:K04347]
105872857  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
109729570  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
105867248  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
109729475  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
105879870  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105867963  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
105861780  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
105864304  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
105865052  ATF2; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
105858535  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
105873936  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
105874305  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
105885209  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
105885942  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
105859108  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
105855129  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
105858143  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
105875869  VEGFA; vascular endothelial growth factor A [KO:K05448]
105878471  VEGFB; vascular endothelial growth factor B isoform X1 [KO:K16858]
105874668  VEGFC; vascular endothelial growth factor C isoform X1 [KO:K05449]
105882414  VEGFD; vascular endothelial growth factor D isoform X1 [KO:K05449]
105855502  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
105874819  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105878531  RELA; transcription factor p65 isoform X1 [KO:K04735]
105857991  NOS2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
105862660  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105855821  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105886063  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
105881219  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105855026  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105877483  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
105877684  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
105882676  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
105868083  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
105873938  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
105870697  mitogen-activated protein kinase 6-like [KO:K04371] [EC:2.7.11.24]
105877796  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
105871124  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
105866549  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
105859286  MMP9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
105861093  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105876768  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105863738  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105883168  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
105866961  NOS1; nitric oxide synthase, brain isoform X1 [KO:K13240] [EC:1.14.13.39]
105865255  EDN1; endothelin-1 [KO:K16366]
105882970  EDNRB; endothelin B receptor [KO:K04198]
105874564  MMP1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
105874586  interstitial collagenase-like [KO:K01388] [EC:3.4.24.7]
105871610  interstitial collagenase-like [KO:K01388] [EC:3.4.24.7]
105874591  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
105869115  TGFB1; transforming growth factor beta-1 isoform X1 [KO:K13375]
105873781  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
105883482  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
105860538  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
105871641  ACTA2; actin, aortic smooth muscle [KO:K12313]
105867267  COL1A2; collagen alpha-2(I) chain [KO:K06236]
105885109  COL1A1; collagen alpha-1(I) chain [KO:K06236]
105877880  COL3A1; collagen alpha-1(III) chain [KO:K19720]
105862838  COL4A3; collagen alpha-3(IV) chain isoform X1 [KO:K06237]
105862840  collagen alpha-4(IV) chain [KO:K06237]
105863390  COL4A5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
105863408  COL4A6; collagen alpha-6(IV) chain isoform X1 [KO:K06237]
105864191  COL4A2; collagen alpha-2(IV) chain [KO:K06237]
105864192  COL4A1; collagen alpha-1(IV) chain isoform X1 [KO:K06237]
109730002  INSL3; LOW QUALITY PROTEIN: insulin-like 3 [KO:K21999]
105864329  RXFP2; relaxin receptor 2 isoform X1 [KO:K04307]
105885464  RLN3; relaxin-3 [KO:K22000]
105867782  RXFP3; relaxin-3 receptor 1 [KO:K08397]
105870668  ADCY1; LOW QUALITY PROTEIN: adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
105859934  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
105884349  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
105866617  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
105867497  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
105884745  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
105882731  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
105859653  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
105861219  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
105878468  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
105872433  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
105880040  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
105861618  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
105878202  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
105885655  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
105861389  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
105861390  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
105885016  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
105885017  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
105860097  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
105874790  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
105864291  mitogen-activated protein kinase 10-like isoform X1 [KO:K04440] [EC:2.7.11.24]
105865754  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
105882585  JUN; transcription factor AP-1 [KO:K04448]
105858849  FOS; proto-oncogene c-Fos [KO:K04379]
105874032  HRAS; GTPase HRas [KO:K02833]
105857286  KRAS; GTPase KRas isoform X1 [KO:K07827]
105878710  NRAS; GTPase NRas [KO:K07828]
105866030  SRC; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
105873192  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
105860825  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
105876163  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
105870730  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
105867678  SOS2; son of sevenless homolog 2 [KO:K03099]
105884529  SOS1; son of sevenless homolog 1 [KO:K03099]
105860366  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
105879284  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
105877217  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
105878936  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
105872838  INSL5; insulin-like peptide INSL5 [KO:K22001]
105873146  RXFP4; relaxin-3 receptor 2 [KO:K08398]
105873965  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
mmur04010  MAPK signaling pathway
mmur04020  Calcium signaling pathway
mmur04024  cAMP signaling pathway
mmur04064  NF-kappa B signaling pathway
mmur04151  PI3K-Akt signaling pathway
mmur04270  Vascular smooth muscle contraction
mmur04350  TGF-beta signaling pathway
mmur04370  VEGF signaling pathway
KO pathway
ko04926   
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