Entry Name Relaxin signaling pathway
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 systemBRITE hierarchy
Pathway map Orthology K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K01388 MMP1; matrix metalloproteinase-1 (interstitial collagenase) [EC:3.4.24.7 ]
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04198 EDNRB; endothelin receptor type B
K04306 RXFP1, LGR7; relaxin family peptide receptor 1
K04307 RXFP2, LGR8; relaxin family peptide receptor 2
K04347 GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04364 GRB2; growth factor receptor-bound protein 2
K04366 RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2 ]
K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2 ]
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04379 FOS; proto-oncogene protein c-fos
K04430 MAP2K4, MKK4; mitogen-activated protein kinase kinase 4 [EC:2.7.12.2 ]
K04431 MAP2K7, MKK7; mitogen-activated protein kinase kinase 7 [EC:2.7.12.2 ]
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04448 JUN; transcription factor AP-1
K04450 ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04500 SMAD2; mothers against decapentaplegic homolog 2
K04534 GNAO, G-ALPHA-O; guanine nucleotide-binding protein G(o) subunit alpha
K04536 GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537 GNB2; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K04538 GNB4; guanine nucleotide-binding protein subunit beta-4
K04539 GNB5; guanine nucleotide-binding protein subunit beta-5
K04540 GNG3; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541 GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542 GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543 GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544 GNG8; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545 GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546 GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04547 GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548 GNGT1; guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549 GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K04630 GNAI; guanine nucleotide-binding protein G(i) subunit alpha
K04632 GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04637 GNA15; guanine nucleotide-binding protein subunit alpha-15
K04734 NFKBIA; NF-kappa-B inhibitor alpha
K04735 RELA; transcription factor p65
K05448 VEGFA; vascular endothelial growth factor A
K05449 VEGFC_D; vascular endothelial growth factor C/D
K05870 CREB1; cyclic AMP-responsive element-binding protein 1
K06236 COL1A; collagen type I alpha
K06237 COL4A; collagen type IV alpha
K06279 SHC1; SHC-transforming protein 1
K07825 GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K07826 GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K07827 KRAS, KRAS2; GTPase KRas
K07994 MMP13; matrix metalloproteinase-13 (collagenase 3) [EC:3.4.24.-]
K08397 RXFP3, RLN3R1; relaxin family peptide receptor 3
K08398 RXFP4, RLN3R2; relaxin family peptide receptor 4
K09047 CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048 CREB3; cyclic AMP-responsive element-binding protein 3
K09049 ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K12313 ACTA2; actin, aortic smooth muscle
K13375 TGFB1; transforming growth factor beta-1
K16858 VEGFB; vascular endothelial growth factor B
K17447 SHC2; SHC-transforming protein 2
K17448 SHC3; SHC-transforming protein 3
K17449 SHC4; SHC-transforming protein 4
K19720 COL3A; collagen type III alpha
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ
Title Relaxin family peptides and their receptors.
Journal Reference 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 Reference 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 Reference 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 Reference 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 Reference Authors Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ
Title Cardiovascular effects of relaxin: from basic science to clinical therapy.
Journal Reference Authors Nistri S, Bani D
Title Relaxin receptors and nitric oxide synthases: search for the missing link.
Journal Reference Authors Samuel CS, Hewitson TD, Unemori EN, Tang ML
Title Drugs of the future: the hormone relaxin.
Journal Reference Authors Sasser JM
Title The emerging role of relaxin as a novel therapeutic pathway in the treatment of chronic kidney disease.
Journal Reference Authors Sarwar M, Du XJ, Dschietzig TB, Summers RJ
Title The actions of relaxin on the human cardiovascular system.
Journal Reference Authors Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ
Title Receptors for relaxin family peptides.
Journal Reference 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 Reference 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 Reference Authors Wilson SS, Ayaz SI, Levy PD
Title Relaxin: a novel agent for the treatment of acute heart failure.
Journal Reference Authors Halls ML, Bathgate RA, Summers RJ
Title Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms.
Journal Reference Authors Kocan M, Ang SY, Summers RJ
Title Orthosteric, Allosteric and Biased Signalling at the Relaxin-3 Receptor RXFP3.
Journal Reference 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 Related ko04064 NF-kappa B signaling pathway
ko04270 Vascular smooth muscle contraction
