KEGG   PATHWAY: anu04926
Entry
anu04926                    Pathway                                
Name
Relaxin signaling pathway - Arvicanthis niloticus (African grass rat)
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
anu04926  Relaxin signaling pathway
anu04926

Organism
Arvicanthis niloticus (African grass rat) [GN:anu]
Gene
117693358  prorelaxin 1-like isoform X1 [KO:K21998]
117707267  Rxfp1; relaxin receptor 1 [KO:K04306]
117722995  Gnao1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
117706851  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
117693315  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
117720623  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
117703732  neuroendocrine secretory protein 55 [KO:K04632]
117703734  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
117708200  Gnb1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
117698102  Gnb2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
117715413  Gnb3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
117706580  Gnb4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
117712557  Gnb5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
117705975  Gng2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
117715090  Gng3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
117713460  Gng4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
117706732  Gng5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
117696108  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5-like [KO:K04542]
117696807  Gng7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
117700356  Gng8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
117708609  Gng10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
117720362  Gng11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
117715105  Gng12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
117723254  Gng14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
117709797  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
117710798  Gng13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
117720345  Gngt1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
117702509  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
117709843  Gngt2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
117717749  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
117723055  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
117706647  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
117705049  Creb1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
117703314  Atf2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
117719125  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
117704442  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
117707799  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
117709015  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
117720532  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
117696466  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
117720600  Creb5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
117724754  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
117722213  Vegfa; vascular endothelial growth factor A isoform X1 [KO:K05448]
117716334  Vegfb; vascular endothelial growth factor B isoform X1 [KO:K16858]
117695345  Vegfd; vascular endothelial growth factor D isoform X1 [KO:K05449]
117721236  Vegfc; vascular endothelial growth factor C [KO:K05449]
117717335  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
117707042  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
117722582  Rela; transcription factor p65 [KO:K04735]
117710677  Nos2; nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
117706649  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
117693421  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
117708986  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
117721973  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
117723761  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
117708961  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
117708435  Prkcz; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
117715476  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
117699009  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
117696143  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
117717711  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
117693439  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
117723004  Mmp2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
117701832  72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
117704142  Mmp9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
117697536  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
117706636  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
117721481  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
117720753  Nos3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
117697935  Nos1; nitric oxide synthase, brain isoform X1 [KO:K13240] [EC:1.14.13.39]
117713961  Edn1; endothelin-1 [KO:K16366]
117705533  Ednrb; endothelin receptor type B [KO:K04198]
117699743  interstitial collagenase B-like [KO:K01388] [EC:3.4.24.7]
117699745  interstitial collagenase B [KO:K01388] [EC:3.4.24.7]
117699856  interstitial collagenase A [KO:K01388] [EC:3.4.24.7]
117699975  Mmp13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
117713589  Tgfb1; transforming growth factor beta-1 proprotein [KO:K13375]
117708549  Tgfbr1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
117693333  Tgfbr2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
117719725  Smad2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
117696974  Acta2; actin, aortic smooth muscle [KO:K12313]
117711501  Col1a1; collagen alpha-1(I) chain [KO:K06236]
117720776  Col1a2; collagen alpha-2(I) chain [KO:K06236]
117705052  Col3a1; collagen alpha-1(III) chain [KO:K19720]
117722158  Col4a3; collagen alpha-3(IV) chain [KO:K06237]
117722162  Col4a4; collagen alpha-4(IV) chain [KO:K06237]
117694087  Col4a5; LOW QUALITY PROTEIN: collagen alpha-5(IV) chain [KO:K06237]
117694384  Col4a6; collagen alpha-6(IV) chain [KO:K06237]
117721417  Col4a1; collagen alpha-1(IV) chain [KO:K06237]
117721418  Col4a2; collagen alpha-2(IV) chain [KO:K06237]
117721501  Insl3; insulin-like 3 [KO:K21999]
117698049  Rxfp2; relaxin receptor 2 isoform X1 [KO:K04307]
117723535  Rln3; relaxin-3 [KO:K22000]
117723652  Rxfp3; relaxin-3 receptor 1 [KO:K08397]
117712590  Adcy1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
117723703  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
117716811  Adcy3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
117704978  Adcy4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
117718589  Adcy6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
117723273  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
117718712  Adcy8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
117710708  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
117712005  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
117703017  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
117703351  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
117703529  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
117709948  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
117710639  Map2k4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
117697775  Map2k7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
117724304  Mapk14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
117724423  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
117718601  Mapk12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
117718602  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
117705037  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
117709966  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
117709069  Jun; transcription factor AP-1 [KO:K04448]
117697448  Fos; proto-oncogene c-Fos [KO:K04379]
117706664  Hras; GTPase HRas isoform X1 [KO:K02833]
117714902  Kras; GTPase KRas isoform X1 [KO:K07827]
117706966  Nras; GTPase NRas [KO:K07828]
117703400  Src; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
117706686  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
117696653  Shc2; SHC-transforming protein 2 [KO:K17447]
117713721  Shc3; SHC-transforming protein 3 [KO:K17448]
117704137  Shc4; SHC-transforming protein 4 [KO:K17449]
117716781  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
117716983  Sos1; son of sevenless homolog 1 isoform X1 [KO:K03099]
117710144  Arrb1; beta-arrestin-1 isoform X1 [KO:K04439]
117711031  Arrb2; beta-arrestin-2 [KO:K04439]
117712744  Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
117711195  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
117709523  Insl5; insulin-like peptide INSL5 [KO:K22001]
117707781  Rxfp4; relaxin-3 receptor 2 [KO:K08398]
117696107  Gna15; guanine nucleotide-binding protein subunit alpha-15 isoform X1 [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
anu04010  MAPK signaling pathway
anu04020  Calcium signaling pathway
anu04024  cAMP signaling pathway
anu04064  NF-kappa B signaling pathway
anu04151  PI3K-Akt signaling pathway
anu04270  Vascular smooth muscle contraction
anu04350  TGF-beta signaling pathway
anu04370  VEGF signaling pathway
KO pathway
ko04926   
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