KEGG   PATHWAY: pleu04926
Entry
pleu04926                   Pathway                                
Name
Relaxin signaling pathway - Peromyscus leucopus (white-footed mouse)
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
pleu04926  Relaxin signaling pathway
pleu04926

Organism
Peromyscus leucopus (white-footed mouse) [GN:pleu]
Gene
114680674  Plcb3; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
114680692  Vegfb; vascular endothelial growth factor B isoform X1 [KO:K16858]
114681254  Gng13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
114681403  Gng8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
114681520  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
114681524  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114681621  Sos1; son of sevenless homolog 1 [KO:K03099]
114681835  Src; proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
114682025  [KO:K04632]
114682029  [KO:K04632]
114682099  Rela; transcription factor p65 [KO:K04735]
114682519  Gng10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
114682732  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
114683205  Nfkb1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
114683622  Gng3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
114683897  Shc4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
114683909  Vegfc; vascular endothelial growth factor C [KO:K05449]
114684032  Pik3cd; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
114684102  Shc2; SHC-transforming protein 2 [KO:K17447]
114684152  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
114684169  Rln3; relaxin-3 [KO:K22000]
114684224  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
114685127  [KO:K02833]
114685202  Gng4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
114685302  Tgfb1; transforming growth factor beta-1 proprotein [KO:K13375]
114686066  Map2k7; LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
114686598  Gng2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
114686769  Gnb2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
114687039  [KO:K07826]
114687553  Arrb2; beta-arrestin-2 [KO:K04439]
114687652  Gng14; putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 [KO:K04347]
114687949  Insl3; insulin-like 3 [KO:K21999]
114687991  [KO:K04374]
114688121  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
114688126  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
114688171  Gna15; LOW QUALITY PROTEIN: guanine nucleotide-binding protein subunit alpha-15 [KO:K04637]
114688303  Gng7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
114688340  [KO:K04545]
114688488  [KO:K02833]
114688889  [KO:K06236]
114688966  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
114689488  Shc3; SHC-transforming protein 3 [KO:K17448]
114689636  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
114689726  Creb5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
114690208  Ednrb; endothelin receptor type B [KO:K04198]
114690390  Gnb5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
114690439  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
114690660  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114690920  [KO:K04674] [EC:2.7.11.30]
114691010  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
114691497  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
114691518  Nos2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
114691745  [KO:K04674] [EC:2.7.11.30]
114691777  Mapk10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
114692100  Edn1; endothelin-1 [KO:K16366]
114692635  Mmp9; matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
114692897  Col1a1; collagen alpha-1(I) chain isoform X1 [KO:K06236]
114692919  Gngt2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
114693019  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
114693020  Mapk11; mitogen-activated protein kinase 11 isoform X5 [KO:K04441] [EC:2.7.11.24]
114693118  Map2k4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
114693378  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
114693442  Gng11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
114693444  Col1a2; LOW QUALITY PROTEIN: collagen alpha-2(I) chain [KO:K06236]
114693493  [KO:K02833]
114693495  Gngt1; guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
114693559  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
114693595  Hras; GTPase HRas isoform X1 [KO:K02833]
114693768  Jun; transcription factor AP-1 [KO:K04448]
114693962  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
114694285  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
114694517  Gnao1; guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
114694533  Mmp2; LOW QUALITY PROTEIN: 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
114694883  Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]
114695104  Col4a2; collagen alpha-2(IV) chain isoform X1 [KO:K06237]
114695105  Col4a1; collagen alpha-1(IV) chain isoform X1 [KO:K06237]
114695335  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
114695341  Gnb4; guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
114696121  Adcy2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
114696435  Col4a3; collagen alpha-3(IV) chain [KO:K06237]
114696436  Col4a4; collagen alpha-4(IV) chain [KO:K06237]
114696553  [KO:K02833]
114697107  Adcy3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
114697724  Adcy8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
114698038  Fos; proto-oncogene c-Fos [KO:K04379]
114698264  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
114698273  Gng5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
114698332  Col4a5; collagen alpha-5(IV) chain isoform X1 [KO:K06237]
114698334  Col4a6; collagen alpha-6(IV) chain [KO:K06237]
114698582  Nras; GTPase NRas [KO:K07828]
114698703  Arrb1; beta-arrestin-1 isoform X1 [KO:K04439]
114699157  Rxfp2; relaxin receptor 2 [KO:K04307]
114699348  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
114699651  Nos1; nitric oxide synthase, brain isoform X2 [KO:K13240] [EC:1.14.13.39]
114699702  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
114699988  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
114700088  Nos3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
114700484  Rxfp1; relaxin receptor 1 isoform X1 [KO:K04306]
114700827  Atf2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
114700920  Gng12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
114702344  Tgfbr1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
114703046  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114703207  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
114703666  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X2 [KO:K05858] [EC:3.1.4.11]
114703672  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
114703850  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
114704332  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
114704841  Adcy5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
114704977  Tgfbr2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
114705057  Creb1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
114705256  Col3a1; collagen alpha-1(III) chain [KO:K19720]
114705300  Vegfa; vascular endothelial growth factor A isoform X1 [KO:K05448]
114705532  Egfr; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
114705711  Vegfd; vascular endothelial growth factor D isoform X1 [KO:K05449]
114705847  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
114705921  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
114706162  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
114706165  Mapk14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
114706924  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
114707024  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
114707479  Insl5; insulin-like peptide INSL5 [KO:K22001]
114707889  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
114707907  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
114708012  Mmp1; interstitial collagenase [KO:K01388] [EC:3.4.24.7]
114708023  Mmp13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
114708228  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
114708277  Prkcz; LOW QUALITY PROTEIN: protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
114708288  Gnb1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
114708477  Kras; GTPase KRas isoform X2 [KO:K07827]
114708501  Adcy7; LOW QUALITY PROTEIN: adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
114708522  Adcy6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
114708701  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
114708827  Gnb3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
114709086  [KO:K04542]
114710523  [KO:K04371] [EC:2.7.11.24]
114710615  Adcy9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
114710804  [KO:K08397]
114710857  [KO:K21998]
114710969  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
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
pleu04010  MAPK signaling pathway
pleu04020  Calcium signaling pathway
pleu04024  cAMP signaling pathway
pleu04064  NF-kappa B signaling pathway
pleu04151  PI3K-Akt signaling pathway
pleu04270  Vascular smooth muscle contraction
pleu04350  TGF-beta signaling pathway
pleu04370  VEGF signaling pathway
KO pathway
ko04926   

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