KEGG   PATHWAY: afz04926
Entry
afz04926                    Pathway                                
Name
Relaxin signaling pathway - Antechinus flavipes (yellow-footed antechinus)
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
afz04926  Relaxin signaling pathway
afz04926

Organism
Antechinus flavipes (yellow-footed antechinus) [GN:afz]
Gene
127555455  prorelaxin H2-like [KO:K21998]
127540999  relaxin receptor 1 isoform X1 [KO:K04306]
127550729  guanine nucleotide-binding protein G(o) subunit alpha isoform X1 [KO:K04534]
127538251  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
127559382  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
127554531  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
127548965  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
127555995  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
127560972  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 [KO:K04537]
127539236  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 [KO:K07825]
127552896  guanine nucleotide-binding protein subunit beta-4 [KO:K04538]
127551163  guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
127539955  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3 [KO:K04540]
127559635  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
127563022  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
127545135  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
127556271  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8 [KO:K04544]
127537835  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
127549287  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11-like [KO:K04546]
127563175  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 isoform X1 [KO:K04347]
127544789  putative guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-14 isoform X1 [KO:K04347]
127543277  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
127546557  guanine nucleotide-binding protein G(T) subunit gamma-T1 [KO:K04548]
127560296  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
127554148  adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
127548938  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
127563015  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
127543087  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
127544835  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
127553178  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
127554549  cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
127538329  LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
127538146  cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
127544947  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
127559872  cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
127539809  cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
127540403  cyclic AMP-responsive element-binding protein 3 [KO:K09048]
127539046  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
127561098  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
127561450  vascular endothelial growth factor A [KO:K05448]
127540655  vascular endothelial growth factor B [KO:K16858]
127541747  vascular endothelial growth factor C [KO:K05449]
127553618  vascular endothelial growth factor D isoform X1 [KO:K05449]
127549751  NF-kappa-B inhibitor alpha [KO:K04734]
127541094  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
127540746  transcription factor p65 isoform X1 [KO:K04735]
127558946  nitric oxide synthase, inducible isoform X1 [KO:K13241] [EC:1.14.13.39]
127555896  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
127552891  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
127554245  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
127563398  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
127558297  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
127545225  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
127555989  protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
127552087  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
127551242  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
127544950  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
127556083  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
127545795  mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
127550719  72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
127550774  matrix metalloproteinase-9 [KO:K01403] [EC:3.4.24.35]
127549861  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
127556193  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
127559596  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
127564122  LOW QUALITY PROTEIN: nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
127545521  nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
127544167  endothelin-1 [KO:K16366]
127553332  endothelin receptor type B [KO:K04198]
127554925  interstitial collagenase-like [KO:K01388] [EC:3.4.24.7]
127554927  collagenase 3 [KO:K07994] [EC:3.4.24.-]
127556228  transforming growth factor beta-1 proprotein [KO:K13375]
127541471  TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
127538005  TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
127543521  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
127552170  actin, aortic smooth muscle [KO:K12313]
127539292  collagen alpha-2(I) chain [KO:K06236]
127560318  collagen alpha-1(I) chain isoform X1 [KO:K06236]
127554480  collagen alpha-1(III) chain isoform X1 [KO:K19720]
127543055  collagen alpha-5(IV) chain [KO:K06237]
127553016  collagen alpha-3(IV) chain [KO:K06237]
127553035  collagen alpha-4(IV) chain isoform X1 [KO:K06237]
127553467  collagen alpha-2(IV) chain [KO:K06237]
127553468  collagen alpha-1(IV) chain [KO:K06237]
127545240  insulin-like 3 isoform X1 [KO:K21999]
127543171  relaxin receptor 1-like [KO:K04307]
127557313  relaxin receptor 2 [KO:K04307]
127540947  relaxin-3 [KO:K22000]
127543439  relaxin-3 receptor 1-like [KO:K08397]
127544134  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
127543614  adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
127548786  adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
127551100  adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
127564773  adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
127550695  adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
127544457  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
127542142  adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
127549225  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
127539641  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
127548499  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
127548500  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
127560569  protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
127560734  dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
127545314  dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
127538834  mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
127538838  mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
127561225  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
127561226  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
127542137  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
127550306  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
127551815  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
127563247  transcription factor Jun [KO:K04448]
127549484  protein c-Fos [KO:K04379]
127540068  GTPase HRas [KO:K02833]
127564364  ras-like protein [KO:K07827]
127564665  ras-like protein [KO:K07827]
127564806  GTPase KRas isoform X1 [KO:K07827]
127564858  GTPase KRas-like [KO:K07827]
127564890  ras-like protein [KO:K07827]
127564892  GTPase NRas-like [KO:K07827]
127541495  ras-like protein [KO:K07827]
127537819  GTPase NRas-like [KO:K07827]
127537860  GTPase NRas-like [KO:K07827]
127538037  ras-like protein [KO:K07827]
127538119  ras-like protein [KO:K07827]
127538128  LOW QUALITY PROTEIN: ras-like protein [KO:K07827]
127538787  ras-like protein [KO:K07827]
127538953  ras-like protein [KO:K07827]
127539191  ras-like protein [KO:K07827]
127539349  GTPase NRas-like [KO:K07827]
127539435  ras-like protein [KO:K07827]
127539441  ras protein let-60-like [KO:K07827]
127541494  ras-like protein [KO:K07828]
127559280  GTPase NRas [KO:K07828]
127538788  GTPase NRas-like [KO:K07828]
127538790  GTPase NRas-like [KO:K07828]
127538791  GTPase NRas-like [KO:K07828]
127538792  GTPase NRas-like [KO:K07828]
127538794  GTPase NRas-like [KO:K07828]
127550415  proto-oncogene tyrosine-protein kinase Src isoform X1 [KO:K05704] [EC:2.7.10.2]
127559844  SHC-transforming protein 1 isoform X1 [KO:K06279]
127545256  SHC-transforming protein 2 isoform X1 [KO:K17447]
127562429  SHC-transforming protein 3 isoform X1 [KO:K17448]
127551137  SHC-transforming protein 4 [KO:K17449]
127549759  son of sevenless homolog 2 isoform X1 [KO:K03099]
127547998  son of sevenless homolog 1 isoform X1 [KO:K03099]
127546692  beta-arrestin-1-like [KO:K04439]
127560926  beta-arrestin-2 [KO:K04439]
127555072  beta-arrestin-1 isoform X1 [KO:K04439]
127553324  epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
127560474  growth factor receptor-bound protein 2 [KO:K04364]
127560519  insulin-like peptide INSL5 [KO:K22001]
127559796  relaxin-3 receptor 2 [KO:K08398]
127545246  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
afz04010  MAPK signaling pathway
afz04020  Calcium signaling pathway
afz04024  cAMP signaling pathway
afz04064  NF-kappa B signaling pathway
afz04151  PI3K-Akt signaling pathway
afz04270  Vascular smooth muscle contraction
afz04350  TGF-beta signaling pathway
afz04370  VEGF signaling pathway
KO pathway
ko04926   
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