KEGG   PATHWAY: ocu04926
Entry
ocu04926                    Pathway                                
Name
Relaxin signaling pathway - Oryctolagus cuniculus (rabbit)
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
ocu04926  Relaxin signaling pathway
ocu04926

Organism
Oryctolagus cuniculus (rabbit) [GN:ocu]
Gene
108178086  prorelaxin [KO:K21998]
100009160  RLN1; relaxin-like protein SQ10 precursor [KO:K21998]
100341333  relaxin-like protein SQ10 [KO:K21998]
100346250  relaxin-like protein SQ10 [KO:K21998]
100346509  relaxin-like protein SQ10 [KO:K21998]
100347029  relaxin-like protein SQ10 [KO:K21998]
108175413  relaxin-like protein SQ10 [KO:K21998]
100345713  RXFP1; relaxin receptor 1 [KO:K04306]
100342283  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
100338391  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100359147  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
100339066  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100008904  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
100346323  neuroendocrine secretory protein 55 [KO:K04632]
100337783  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
127489280  LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
100356799  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
100346625  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
100338332  guanine nucleotide-binding protein subunit beta-4 isoform X2 [KO:K04538]
100008941  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
100352954  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
100348350  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 isoform X2 [KO:K04540]
103350926  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
108178480  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
100355417  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
108177128  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
100342201  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
108176185  GNG14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
103350153  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
127489712  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
100342450  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
108178552  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
100009315  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100008815  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100342212  cAMP-dependent protein kinase catalytic subunit beta isoform X3 [KO:K04345] [EC:2.7.11.11]
100351999  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100355367  cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100339383  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100358175  cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100343130  cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X2 [KO:K09048]
100345475  cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100357876  cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100357483  cyclic AMP-responsive element-binding protein 5 isoform X3 [KO:K09047]
100357489  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
127493063  cyclic AMP-dependent transcription factor ATF-6 beta-like isoform X1 [KO:K09049]
100008899  vascular endothelial growth factor A [KO:K05448]
127487461  vascular endothelial growth factor B isoform X1 [KO:K16858]
100338211  vascular endothelial growth factor C isoform X1 [KO:K05449]
100338090  vascular endothelial growth factor D isoform X1 [KO:K05449]
100357341  NF-kappa-B inhibitor alpha [KO:K04734]
100349426  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
127485184  transcription factor p65 isoform X1 [KO:K04735]
100008833  nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
100348663  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100345181  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100337822  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100357841  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100345250  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100009538  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
100347407  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100009316  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
127489461  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:2.7.12.2]
100347345  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100348561  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100009000  MMP2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]
100008993  MMP9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
100342852  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100353706  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
127486116  RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100009498  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
127493711  nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
100009243  NOS1; nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
100009270  EDN1; endothelin-1 precursor [KO:K16366]
100009477  EDNRB; endothelin receptor type B precursor [KO:K04198]
100009110  MMP1; interstitial collagenase precursor [KO:K01388] [EC:3.4.24.7]
100008685  MMP13; collagenase 3 precursor [KO:K07994] [EC:3.4.24.-]
100352301  LOW QUALITY PROTEIN: transforming growth factor beta-1 proprotein [KO:K13375]
103345448  transforming growth factor beta-1 proprotein isoform X9 [KO:K13375]
100008645  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
100345812  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100344335  TGFBR2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]
100359137  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100009271  ACTA2; actin, aortic smooth muscle [KO:K12313]
100347598  collagen alpha-1(I) chain isoform X1 [KO:K06236]
100008997  COL1A2; collagen alpha-2(I) chain precursor [KO:K06236]
100009177  collagen alpha-1(III) chain [KO:K19720]
100358256  collagen alpha-1(IV) chain [KO:K06237]
100358522  LOW QUALITY PROTEIN: collagen alpha-2(IV) chain [KO:K06237]
100338437  collagen alpha-6(IV) chain [KO:K06237]
100357427  collagen alpha-5(IV) chain [KO:K06237]
100357900  collagen alpha-4(IV) chain isoform X2 [KO:K06237]
108176892  collagen alpha-3(IV) chain isoform X1 [KO:K06237]
100354567  relaxin receptor 2 isoform X1 [KO:K04307]
100144339  RLN3; relaxin-3 precursor [KO:K22000]
100356882  relaxin-3 receptor 1 [KO:K08397]
103347035  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100009201  adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100343958  adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
100346742  adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100354934  adenylate cyclase type 6 isoform X8 [KO:K08046] [EC:4.6.1.1]
100357357  adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100337882  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100340877  adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100348672  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X4 [KO:K05858] [EC:3.1.4.11]
100350395  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100341512  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858] [EC:3.1.4.11]
103347536  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100037720  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100344852  dual specificity mitogen-activated protein kinase kinase 4 isoform X2 [KO:K04430] [EC:2.7.12.2]
103345313  dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
100350614  mitogen-activated protein kinase 12 isoform X2 [KO:K04441] [EC:2.7.11.24]
103346035  mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
100344161  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100341695  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100346929  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100342664  mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
100337999  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100008856  JUN; transcription factor Jun [KO:K04448]
100338345  protein c-Fos [KO:K04379]
127486605  GTPase HRas isoform X1 [KO:K02833]
100347487  GTPase KRas isoform X1 [KO:K07827]
127489236  GTPase KRas-like [KO:K07827]
100344241  GTPase NRas [KO:K07828]
100341599  proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
100342812  SHC-transforming protein 1 isoform X2 [KO:K06279]
100353992  SHC-transforming protein 3 isoform X2 [KO:K17448]
100350676  SHC-transforming protein 4 isoform X2 [KO:K17449]
100356615  son of sevenless homolog 1 isoform X1 [KO:K03099]
100346391  son of sevenless homolog 2 isoform X1 [KO:K03099]
100341204  beta-arrestin-2 [KO:K04439]
100009235  beta-arrestin-1 isoform X1 [KO:K04439]
100008806  epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100342500  growth factor receptor-bound protein 2 [KO:K04364]
100141505  INSL5; insulin-like peptide INSL5 precursor [KO:K22001]
100347249  relaxin-3 receptor 2 [KO:K08398]
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
ocu04010  MAPK signaling pathway
ocu04020  Calcium signaling pathway
ocu04024  cAMP signaling pathway
ocu04064  NF-kappa B signaling pathway
ocu04151  PI3K-Akt signaling pathway
ocu04270  Vascular smooth muscle contraction
ocu04350  TGF-beta signaling pathway
ocu04370  VEGF signaling pathway
KO pathway
ko04926   
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