KEGG   PATHWAY: cuca04371
Entry
cuca04371                   Pathway                                
Name
Apelin signaling pathway - Cuculus canorus (common cuckoo)
Description
Apelin is an endogenous peptide capable of binding the apelin receptor (APJ), which was originally described as an orphan G-protein-coupled receptor. Apelin and APJ are widely expressed in various tissues and organ systems. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, cell proliferation and energy metabolism regulation. On the other hand, this ligand receptor couple is also involved in several pathologies including diabetes, obesity, cardiovascular disease and cancer.
Class
Environmental Information Processing; Signal transduction
Pathway map
cuca04371  Apelin signaling pathway
cuca04371

Other DBs
GO: 0060183
Organism
Cuculus canorus (common cuckoo) [GN:cuca]
Gene
104065956  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
104067554  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
104061819  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
104067688  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
104055011  ADCY6; LOW QUALITY PROTEIN: adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
104068389  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
104058511  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
104068131  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
104055210  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
104060513  APLN; apelin [KO:K05225]
104062054  APLNR; apelin receptor [KO:K04174]
104066031  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
104066710  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
104062293  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
104059828  GNB1; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 [KO:K04536]
104064366  GNB3; guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 isoform X1 [KO:K07825]
104057849  GNB4; guanine nucleotide-binding protein subunit beta-4 isoform X1 [KO:K04538]
104055250  GNB5; guanine nucleotide-binding protein subunit beta-5 [KO:K04539]
104057421  GNG2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 [KO:K07826]
104060348  GNG4; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4 [KO:K04541]
104055224  GNG5; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 [KO:K04542]
104065761  GNG7; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7 [KO:K04543]
104065718  GNG10; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10 [KO:K04545]
104057515  GNG11; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11 [KO:K04546]
104066569  GNG12; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12 [KO:K04347]
104060386  GNG13; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13 [KO:K04547]
104068261  GNGT2; guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2 [KO:K04549]
104058397  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
104064431  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
104055376  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
104055439  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
104063584  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
104067151  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
104067088  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
104062467  ryanodine receptor 2 [KO:K04962]
104059034  RYR3; ryanodine receptor 3 [KO:K04963]
104059610  CALM1; calmodulin [KO:K02183]
104065198  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
104061442  calmodulin, striated muscle [KO:K02183]
104062215  CALM2; calmodulin [KO:K02183]
104056123  NOS1; LOW QUALITY PROTEIN: nitric oxide synthase, brain [KO:K13240] [EC:1.14.13.39]
104064984  NOS2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
104056824  PRKCE; protein kinase C epsilon type [KO:K18050] [EC:2.7.11.13]
104056314  SLC9A1; sodium/hydrogen exchanger 1 [KO:K05742]
104063200  sodium/calcium exchanger 2-like [KO:K05849]
104055465  SLC8A1; sodium/calcium exchanger 1 [KO:K05849]
104061651  SLC8A3; sodium/calcium exchanger 3 isoform X1 [KO:K05849]
104055738  MYLK3; myosin light chain kinase 3 [KO:K00907] [EC:2.7.11.18]
104060871  MYLK2; myosin light chain kinase 2, skeletal/cardiac muscle [KO:K00907] [EC:2.7.11.18]
104066859  MYLK4; myosin light chain kinase family member 4 [KO:K00907] [EC:2.7.11.18]
104067687  MYLK; myosin light chain kinase, smooth muscle isoform X1 [KO:K00907] [EC:2.7.11.18]
104064904  myosin light chain kinase, smooth muscle-like [KO:K00907] [EC:2.7.11.18]
104058811  MYL2; myosin regulatory light chain 2, ventricular/cardiac muscle isoform [KO:K10351]
104055033  MYL3; myosin light chain 3 [KO:K12749]
104054382  MYL4; myosin light chain 4 [KO:K12750]
104068924  HRAS; GTPase HRas [KO:K02833]
104067113  KRAS; GTPase KRas isoform X1 [KO:K07827]
104067100  NRAS; GTPase NRas [KO:K07828]
104068950  RRAS2; ras-related protein R-Ras2 [KO:K07830]
104067700  MRAS; ras-related protein M-Ras [KO:K07831]
104064618  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
104065161  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
104056230  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
104064060  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
104063362  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
104064956  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
104063175  LOW QUALITY PROTEIN: 40S ribosomal protein S6-like [KO:K02991]
104064831  40S ribosomal protein S6 [KO:K02991]
104056069  PIK3CG; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform [KO:K21289] [EC:2.7.1.153]
104060769  PIK3R6; phosphoinositide 3-kinase regulatory subunit 6 [KO:K21290]
104060773  PIK3R5; phosphoinositide 3-kinase regulatory subunit 5 [KO:K21290]
104062320  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104057828  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104058178  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
104060550  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
104060763  EGR1; early growth response protein 1 [KO:K09203]
104058069  SPP1; osteopontin [KO:K06250]
104055380  JAG1; LOW QUALITY PROTEIN: protein jagged-1 [KO:K06052]
104062258  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
104068951  PDE3B; LOW QUALITY PROTEIN: cGMP-inhibited 3',5'-cyclic phosphodiesterase B [KO:K13296] [EC:3.1.4.17]
104067509  PIK3C3; phosphatidylinositol 3-kinase catalytic subunit type 3 [KO:K00914] [EC:2.7.1.137]
104067633  PIK3R4; phosphoinositide 3-kinase regulatory subunit 4 [KO:K08333] [EC:2.7.11.1]
104054389  BECN1; beclin-1 [KO:K08334]
104063248  MAP1LC3A; microtubule-associated proteins 1A/1B light chain 3A [KO:K10435]
104063348  microtubule-associated proteins 1A/1B light chain 3C-like [KO:K10435]
104061314  MAP1LC3B; microtubule-associated proteins 1A/1B light chain 3B [KO:K10435]
104057967  MAP1LC3C; microtubule-associated proteins 1A/1B light chain 3C [KO:K10435]
104059661  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
104066577  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
104063311  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
104064259  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X1 [KO:K07199]
104055018  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
104056329  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
104056992  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
104059690  PLIN1; perilipin-1 [KO:K08768]
104063295  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
104061365  NRF1; nuclear respiratory factor 1 [KO:K11831]
104066520  TFAM; transcription factor A, mitochondrial [KO:K11830]
104060983  KLF2; Krueppel-like factor 2 [KO:K17845]
104068674  SPHK1; sphingosine kinase 1 [KO:K04718] [EC:2.7.1.91]
104061899  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
104058747  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
104065755  calcium/calmodulin-dependent protein kinase type IV-like [KO:K05869] [EC:2.7.11.17]
104068297  HDAC5; histone deacetylase 5 [KO:K11406] [EC:3.5.1.98]
104056943  HDAC4; histone deacetylase 4 [KO:K11406] [EC:3.5.1.98]
104062936  MEF2A; myocyte-specific enhancer factor 2A isoform X1 [KO:K09260]
104065826  myocyte-specific enhancer factor 2B-like [KO:K09261]
104061059  MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454]
104062840  MEF2D; myocyte-specific enhancer factor 2D [KO:K09262]
104055753  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
104063566  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
104065164  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
104061405  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
104067878  ACTA2; actin, aortic smooth muscle isoform X1 [KO:K12313]
104055001  CDH1; cadherin-1 [KO:K05689]
104059526  connective tissue growth factor-like [KO:K06827]
104062589  CTGF; connective tissue growth factor [KO:K06827]
104063418  AGTR1; type-1 angiotensin II receptor [KO:K04166]
104068532  PLAT; tissue-type plasminogen activator [KO:K01343] [EC:3.4.21.68]
Compound
C00076  Calcium cation
C00080  H+
C00165  Diacylglycerol
C00290  Fibrin
C00533  Nitric oxide
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C06124  Sphingosine 1-phosphate
Reference
PMID:26143239
  Authors
Yang P, Maguire JJ, Davenport AP
  Title
Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system.
  Journal
Trends Pharmacol Sci 36:560-7 (2015)
DOI:10.1016/j.tips.2015.06.002
Reference
PMID:22140623
  Authors
Andersen CU, Hilberg O, Mellemkjaer S, Nielsen-Kudsk JE, Simonsen U
  Title
Apelin and pulmonary hypertension.
  Journal
Pulm Circ 1:334-46 (2011)
DOI:10.4103/2045-8932.87299
Reference
PMID:25275559
  Authors
Chapman NA, Dupre DJ, Rainey JK
  Title
The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR.
  Journal
Biochem Cell Biol 92:431-40 (2014)
DOI:10.1139/bcb-2014-0072
Reference
PMID:18272138
  Authors
Japp AG, Newby DE
  Title
The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential.
  Journal
Biochem Pharmacol 75:1882-92 (2008)
DOI:10.1016/j.bcp.2007.12.015
Reference
PMID:25652330
  Authors
Folino A, Montarolo PG, Samaja M, Rastaldo R
  Title
Effects of apelin on the cardiovascular system.
  Journal
Heart Fail Rev 20:505-18 (2015)
DOI:10.1007/s10741-015-9475-x
Reference
PMID:23943882
  Authors
O'Carroll AM, Lolait SJ, Harris LE, Pope GR
  Title
The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis.
  Journal
J Endocrinol 219:R13-35 (2013)
DOI:10.1530/JOE-13-0227
Reference
PMID:23973488
  Authors
Liu QF, Yu HW, You L, Liu MX, Li KY, Tao GZ
  Title
Apelin-13-induced proliferation and migration induced of rat vascular smooth muscle cells is mediated by the upregulation of Egr-1.
  Journal
Biochem Biophys Res Commun 439:235-40 (2013)
DOI:10.1016/j.bbrc.2013.08.051
Reference
PMID:26254105
  Authors
Novakova V, Sandhu GS, Dragomir-Daescu D, Klabusay M
  Title
Apelinergic system in endothelial cells and its role in angiogenesis in myocardial ischemia.
  Journal
Vascul Pharmacol 76:1-10 (2016)
DOI:10.1016/j.vph.2015.08.005
Reference
PMID:21725702
  Authors
Castan-Laurell I, Dray C, Attane C, Duparc T, Knauf C, Valet P
  Title
Apelin, diabetes, and obesity.
  Journal
Endocrine 40:1-9 (2011)
DOI:10.1007/s12020-011-9507-9
Reference
PMID:23924696
  Authors
Li L, Li L, Xie F, Zhang Z, Guo Y, Tang G, Lv D, Lu Q, Chen L, Li J
  Title
Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13-induced vascular smooth muscle cells proliferation.
  Journal
Acta Biochim Biophys Sin (Shanghai) 45:875-81 (2013)
DOI:10.1093/abbs/gmt085
Reference
PMID:24990699
  Authors
Wu D, He L, Chen L
  Title
Apelin/APJ system: a promising therapy target for hypertension.
  Journal
Mol Biol Rep 41:6691-703 (2014)
DOI:10.1007/s11033-014-3552-4
Reference
PMID:20539939
  Authors
Liu C, Su T, Li F, Li L, Qin X, Pan W, Feng F, Chen F, Liao D, Chen L
  Title
PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin-13.
  Journal
Acta Biochim Biophys Sin (Shanghai) 42:396-402 (2010)
DOI:10.1093/abbs/gmq035
Reference
PMID:26607438
  Authors
Xie F, Liu W, Feng F, Li X, He L, Lv D, Qin X, Li L, Li L, Chen L
  Title
Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy.
  Journal
Acta Biochim Biophys Sin (Shanghai) 47:969-80 (2015)
DOI:10.1093/abbs/gmv111
Reference
PMID:27979574
  Authors
Lu L, Wu D, Li L, Chen L
  Title
Apelin/APJ system: A bifunctional target for cardiac hypertrophy.
  Journal
Int J Cardiol 230:164-170 (2017)
DOI:10.1016/j.ijcard.2016.11.215
Reference
PMID:16182514
  Authors
Carmen GY, Victor SM
  Title
Signalling mechanisms regulating lipolysis.
  Journal
Cell Signal 18:401-8 (2006)
DOI:10.1016/j.cellsig.2005.08.009
Reference
PMID:27650065
  Authors
Hu H, He L, Li L, Chen L
  Title
Apelin/APJ system as a therapeutic target in diabetes and its complications.
  Journal
Mol Genet Metab 119:20-7 (2016)
DOI:10.1016/j.ymgme.2016.07.012
Reference
PMID:25914650
  Authors
Bertrand C, Valet P, Castan-Laurell I
  Title
Apelin and energy metabolism.
  Journal
Front Physiol 6:115 (2015)
DOI:10.3389/fphys.2015.00115
Reference
PMID:26385179
  Authors
Yao F, Lv YC, Zhang M, Xie W, Tan YL, Gong D, Cheng HP, Liu D, Li L, Liu XY, Zheng XL, Tang CK
  Title
Apelin-13 impedes foam cell formation by activating Class III PI3K/Beclin-1-mediated autophagic pathway.
  Journal
Biochem Biophys Res Commun 466:637-43 (2015)
DOI:10.1016/j.bbrc.2015.09.045
Reference
PMID:22842084
  Authors
Than A, Cheng Y, Foh LC, Leow MK, Lim SC, Chuah YJ, Kang Y, Chen P
  Title
Apelin inhibits adipogenesis and lipolysis through distinct molecular pathways.
  Journal
Mol Cell Endocrinol 362:227-41 (2012)
DOI:10.1016/j.mce.2012.07.002
Reference
PMID:24055369
  Authors
Yu XH, Tang ZB, Liu LJ, Qian H, Tang SL, Zhang DW, Tian GP, Tang CK
  Title
Apelin and its receptor APJ in cardiovascular diseases.
  Journal
Clin Chim Acta 428:1-8 (2014)
DOI:10.1016/j.cca.2013.09.001
Reference
PMID:25931124
  Authors
Than A, He HL, Chua SH, Xu D, Sun L, Leow MK, Chen P
  Title
Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes.
  Journal
J Biol Chem 290:14679-91 (2015)
DOI:10.1074/jbc.M115.643817
Reference
PMID:25139773
  Authors
Fu J, Li Z, Zhang H, Mao Y, Wang A, Wang X, Zou Z, Zhang X
  Title
Molecular pathways regulating the formation of brown-like adipocytes in white adipose tissue.
  Journal
Diabetes Metab Res Rev 31:433-52 (2015)
DOI:10.1002/dmrr.2600
Reference
PMID:21464822
  Authors
Aharoni-Simon M, Hann-Obercyger M, Pen S, Madar Z, Tirosh O
  Title
Fatty liver is associated with impaired activity of PPARgamma-coactivator 1alpha (PGC1alpha) and mitochondrial biogenesis in mice.
  Journal
Lab Invest 91:1018-28 (2011)
DOI:10.1038/labinvest.2011.55
Reference
PMID:22995518
  Authors
McLean DL, Kim J, Kang Y, Shi H, Atkins GB, Jain MK, Chun HJ
  Title
Apelin/APJ signaling is a critical regulator of statin effects in vascular endothelial cells--brief report.
  Journal
Arterioscler Thromb Vasc Biol 32:2640-3 (2012)
DOI:10.1161/ATVBAHA.112.300317
Reference
PMID:22028387
  Authors
Pchejetski D, Foussal C, Alfarano C, Lairez O, Calise D, Guilbeau-Frugier C, Schaak S, Seguelas MH, Wanecq E, Valet P, Parini A, Kunduzova O
  Title
Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1.
  Journal
Eur Heart J 33:2360-9 (2012)
DOI:10.1093/eurheartj/ehr389
Reference
PMID:26944568
  Authors
Huang S, Chen L, Lu L, Li L
  Title
The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis.
  Journal
Clin Chim Acta 456:81-8 (2016)
DOI:10.1016/j.cca.2016.02.025
Reference
PMID:19093215
  Authors
Liu G, Han J, Profirovic J, Strekalova E, Voyno-Yasenetskaya TA
  Title
Galpha13 regulates MEF2-dependent gene transcription in endothelial cells: role in angiogenesis.
  Journal
Angiogenesis 12:1-15 (2009)
DOI:10.1007/s10456-008-9123-3
Reference
PMID:23603510
  Authors
Kang Y, Kim J, Anderson JP, Wu J, Gleim SR, Kundu RK, McLean DL, Kim JD, Park H, Jin SW, Hwa J, Quertermous T, Chun HJ
  Title
Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development.
  Journal
Circ Res 113:22-31 (2013)
DOI:10.1161/CIRCRESAHA.113.301324
Reference
PMID:25164121
  Authors
Wang LY, Diao ZL, Zhang DL, Zheng JF, Zhang QD, Ding JX, Liu WH
  Title
The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis.
  Journal
Amino Acids 46:2693-704 (2014)
DOI:10.1007/s00726-014-1826-8
Reference
PMID:26756969
  Authors
Zhou Y, Deng L, Zhao D, Chen L, Yao Z, Guo X, Liu X, Lv L, Leng B, Xu W, Qiao G, Shan H
  Title
MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin-13.
  Journal
J Cell Mol Med 20:495-505 (2016)
DOI:10.1111/jcmm.12754
Reference
PMID:27825851
  Authors
Zhong JC, Zhang ZZ, Wang W, McKinnie SM, Vederas JC, Oudit GY
  Title
Targeting the apelin pathway as a novel therapeutic approach for cardiovascular diseases.
  Journal
Biochim Biophys Acta 1863:1942-1950 (2017)
DOI:10.1016/j.bbadis.2016.11.007
Related
pathway
cuca04010  MAPK signaling pathway
cuca04020  Calcium signaling pathway
cuca04140  Autophagy - animal
cuca04150  mTOR signaling pathway
cuca04270  Vascular smooth muscle contraction
cuca04530  Tight junction
KO pathway
ko04371   
LinkDB

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