KEGG   PATHWAY: hsa04926
Entry
hsa04926                    Pathway                                
Name
Relaxin signaling pathway - Homo sapiens (human)
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
hsa04926  Relaxin signaling pathway
hsa04926

Drug
D03517  Cipemastat (USAN/INN)
D10488  Serelaxin (USAN/INN)
D12181  Edasalonexent (USAN/INN)
D12768  Ficerafusp alfa (USAN)
D12783  Volenrelaxin (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
10000  AKT3; RAC-gamma serine/threonine-protein kinase isoform 1 [KO:K04456] [EC:2.7.11.1]
10022  INSL5; insulin-like peptide INSL5 precursor [KO:K22001]
10488  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
10681  GNB5; guanine nucleotide-binding protein subunit beta-5 isoform b [KO:K04539]
107  ADCY1; adenylate cyclase type 1 isoform 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
109  ADCY3; adenylate cyclase type 3 isoform 2 [KO:K08043] [EC:4.6.1.1]
110117499  P3R3URF-PIK3R3; LOC110117498-PIK3R3 readthrough [KO:K02649]
111  ADCY5; adenylate cyclase type 5 isoform 1 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase type 6 isoform 1 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase type 7 isoform 1 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
117579  RLN3; relaxin-3 preproprotein [KO:K22000]
122042  RXFP2; relaxin receptor 2 isoform 1 [KO:K04307]
1277  COL1A1; collagen alpha-1(I) chain preproprotein [KO:K06236]
1278  COL1A2; collagen alpha-2(I) chain precursor [KO:K06236]
1281  COL3A1; collagen alpha-1(III) chain preproprotein [KO:K19720]
1282  COL4A1; collagen alpha-1(IV) chain isoform 1 preproprotein [KO:K06237]
1284  COL4A2; collagen alpha-2(IV) chain preproprotein [KO:K06237]
1285  COL4A3; collagen alpha-3(IV) chain precursor [KO:K06237]
1286  COL4A4; collagen alpha-4(IV) chain precursor [KO:K06237]
1287  COL4A5; collagen alpha-5(IV) chain isoform 1 precursor [KO:K06237]
1288  COL4A6; collagen alpha-6(IV) chain isoform A precursor [KO:K06237]
1385  CREB1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
1386  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform 1 [KO:K04450]
1388  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform a [KO:K09049]
1432  MAPK14; mitogen-activated protein kinase 14 isoform 2 [KO:K04441] [EC:2.7.11.24]
148327  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
1906  EDN1; endothelin-1 isoform 1 preproprotein [KO:K16366]
1910  EDNRB; endothelin receptor type B isoform 1 precursor [KO:K04198]
1956  EGFR; epidermal growth factor receptor isoform a precursor [KO:K04361] [EC:2.7.10.1]
196883  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
207  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
208  AKT2; RAC-beta serine/threonine-protein kinase isoform 1 [KO:K04456] [EC:2.7.11.1]
2277  VEGFD; vascular endothelial growth factor D preproprotein [KO:K05449]
23236  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform a [KO:K05858] [EC:3.1.4.11]
2353  FOS; protein c-Fos [KO:K04379]
25759  SHC2; SHC-transforming protein 2 isoform 1 [KO:K17447]
2769  GNA15; guanine nucleotide-binding protein subunit alpha-15 [KO:K04637]
2770  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform 1 [KO:K04630]
2771  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform 1 [KO:K04630]
2773  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
2775  GNAO1; guanine nucleotide-binding protein G(o) subunit alpha isoform a [KO:K04534]
2778  GNAS; protein GNAS isoform XLas [KO:K04632]
2782  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 isoform 1 [KO:K04536]
2783  GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
2784  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform 1 [KO:K07825]
2785  GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
2786  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
2787  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
2788  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
2790  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
2791  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 precursor [KO:K04546]
2792  GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1 precursor [KO:K04548]
2793  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
2885  GRB2; growth factor receptor-bound protein 2 isoform 1 [KO:K04364]
3265  HRAS; GTPase HRas isoform 1 [KO:K02833]
339403  RXFP4; relaxin-3 receptor 2 [KO:K08398]
3640  INSL3; insulin-like 3 isoform 2 precursor [KO:K21999]
3725  JUN; transcription factor Jun [KO:K04448]
3845  KRAS; GTPase KRas isoform a [KO:K07827]
399694  SHC4; SHC-transforming protein 4 [KO:K17449]
408  ARRB1; beta-arrestin-1 isoform A [KO:K04439]
4087  SMAD2; mothers against decapentaplegic homolog 2 isoform 1 [KO:K04500]
409  ARRB2; beta-arrestin-2 isoform 1 [KO:K04439]
4312  MMP1; interstitial collagenase isoform 1 preproprotein [KO:K01388] [EC:3.4.24.7]
4313  MMP2; 72 kDa type IV collagenase isoform 1 preproprotein [KO:K01398] [EC:3.4.24.24]
4318  MMP9; matrix metalloproteinase-9 preproprotein [KO:K01403] [EC:3.4.24.35]
4322  MMP13; collagenase 3 preproprotein [KO:K07994] [EC:3.4.24.-]
468  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
4790  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform 2 proprotein [KO:K02580]
4792  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
4842  NOS1; nitric oxide synthase 1 isoform 1 [KO:K13240] [EC:1.14.13.39]
4843  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
4846  NOS3; nitric oxide synthase 3 isoform 1 [KO:K13242] [EC:1.14.13.39]
4893  NRAS; GTPase NRas [KO:K07828]
51289  RXFP3; relaxin-3 receptor 1 [KO:K08397]
51764  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
5290  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform 1 [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform 1 [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform 1 [KO:K02649]
5296  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
5330  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform 1 [KO:K05858] [EC:3.1.4.11]
5331  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform 1 [KO:K05858] [EC:3.1.4.11]
5332  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform b [KO:K05858] [EC:3.1.4.11]
53358  SHC3; SHC-transforming protein 3 [KO:K17448]
54331  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 precursor [KO:K07826]
5566  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform Calpha1 [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform 2 [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
5578  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
5590  PRKCZ; protein kinase C zeta type isoform 1 [KO:K18952] [EC:2.7.11.13]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 isoform 1 [KO:K04371] [EC:2.7.11.24]
55970  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
5599  MAPK8; mitogen-activated protein kinase 8 isoform alpha2 [KO:K04440] [EC:2.7.11.24]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 isoform alpha2 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 isoform 1 [KO:K04440] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
5604  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform 1 [KO:K04369] [EC:2.7.12.2]
5609  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform 3 [KO:K04431] [EC:2.7.12.2]
5894  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform b [KO:K04366] [EC:2.7.11.1]
59  ACTA2; actin, aortic smooth muscle isoform 1 [KO:K12313]
59345  GNB4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
59350  RXFP1; relaxin receptor 1 isoform 1 precursor [KO:K04306]
5970  RELA; transcription factor p65 isoform 1 [KO:K04735]
6013  RLN1; prorelaxin H1 preproprotein [KO:K21998]
6019  RLN2; prorelaxin H2 isoform 1 preproprotein [KO:K21998]
6300  MAPK12; mitogen-activated protein kinase 12 isoform 1 [KO:K04441] [EC:2.7.11.24]
6416  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform 1 [KO:K04430] [EC:2.7.12.2]
6464  SHC1; SHC-transforming protein 1 isoform 1 [KO:K06279]
64764  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform 1 [KO:K09048]
6654  SOS1; son of sevenless homolog 1 isoform 1 [KO:K03099]
6655  SOS2; son of sevenless homolog 2 isoform 1 [KO:K03099]
6714  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
7040  TGFB1; transforming growth factor beta-1 proprotein preproprotein [KO:K13375]
7046  TGFBR1; TGF-beta receptor type-1 isoform 1 precursor [KO:K04674] [EC:2.7.11.30]
7048  TGFBR2; TGF-beta receptor type-2 isoform B precursor [KO:K04388] [EC:2.7.11.30]
7422  VEGFA; vascular endothelial growth factor A, long form isoform b [KO:K05448]
7423  VEGFB; vascular endothelial growth factor B isoform VEGFB-186 precursor [KO:K16858]
7424  VEGFC; vascular endothelial growth factor C preproprotein [KO:K05449]
84699  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform a [KO:K09048]
8503  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform 1 [KO:K02649]
90993  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform 1 [KO:K09048]
94235  GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
9586  CREB5; cyclic AMP-responsive element-binding protein 5 isoform alpha [KO:K09047]
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
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04024  cAMP signaling pathway
hsa04064  NF-kappa B signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04270  Vascular smooth muscle contraction
hsa04350  TGF-beta signaling pathway
hsa04370  VEGF signaling pathway
KO pathway
ko04926   

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