KEGG   PATHWAY: hsa04371
hsa04371                    Pathway                                
Apelin signaling pathway - Homo sapiens (human)
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.
Environmental Information Processing; Signal transduction
Pathway map
hsa04371  Apelin signaling pathway

D00231  Inamrinone (USP)
D00417  Milrinone (JAN/USP/INN)
D01133  Pimobendan (JAN/USAN/INN)
D01238  Bucladesine sodium (JAN)
D01697  Colforsin daropate hydrochloride (JAN)
D02084  Inamrinone ethylenelactate
D02085  Milrinone lactate
D04004  Enoximone (USAN/INN)
D04508  Imazodan hydrochloride (USAN)
D04529  Indolidan (USAN/INN)
D04628  Isomazole hydrochloride (USAN)
D04720  Levosimendan (USAN/INN)
D04751  Lixazinone sulfate (USAN)
D07546  Bucladesine (INN)
D10969  Pamrevlumab (USAN/INN)
Other DBs
GO: 0060183
Homo sapiens (human) [GN:hsa]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:]
55811  ADCY10; adenylate cyclase 10 [KO:K11265] [EC:]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:]
3991  LIPE; lipase E, hormone sensitive type [KO:K07188] [EC:]
8862  APLN; apelin [KO:K05225]
100506013  APELA; apelin receptor early endogenous ligand [KO:K25355]
187  APLNR; apelin receptor [KO:K04174]
2770  GNAI1; G protein subunit alpha i1 [KO:K04630]
2773  GNAI3; G protein subunit alpha i3 [KO:K04630]
2771  GNAI2; G protein subunit alpha i2 [KO:K04630]
2782  GNB1; G protein subunit beta 1 [KO:K04536]
2783  GNB2; G protein subunit beta 2 [KO:K04537]
2784  GNB3; G protein subunit beta 3 [KO:K07825]
59345  GNB4; G protein subunit beta 4 [KO:K04538]
10681  GNB5; G protein subunit beta 5 [KO:K04539]
54331  GNG2; G protein subunit gamma 2 [KO:K07826]
2785  GNG3; G protein subunit gamma 3 [KO:K04540]
2786  GNG4; G protein subunit gamma 4 [KO:K04541]
2787  GNG5; G protein subunit gamma 5 [KO:K04542]
2788  GNG7; G protein subunit gamma 7 [KO:K04543]
94235  GNG8; G protein subunit gamma 8 [KO:K04544]
2790  GNG10; G protein subunit gamma 10 [KO:K04545]
2791  GNG11; G protein subunit gamma 11 [KO:K04546]
55970  GNG12; G protein subunit gamma 12 [KO:K04347]
51764  GNG13; G protein subunit gamma 13 [KO:K04547]
2792  GNGT1; G protein subunit gamma transducin 1 [KO:K04548]
2793  GNGT2; G protein subunit gamma transducin 2 [KO:K04549]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:]
3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
3709  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
6261  RYR1; ryanodine receptor 1 [KO:K04961]
6262  RYR2; ryanodine receptor 2 [KO:K04962]
6263  RYR3; ryanodine receptor 3 [KO:K04963]
810  CALML3; calmodulin like 3 [KO:K02183]
805  CALM2; calmodulin 2 [KO:K02183]
808  CALM3; calmodulin 3 [KO:K02183]
801  CALM1; calmodulin 1 [KO:K02183]
163688  CALML6; calmodulin like 6 [KO:K02183]
51806  CALML5; calmodulin like 5 [KO:K02183]
91860  CALML4; calmodulin like 4 [KO:K02183]
4842  NOS1; nitric oxide synthase 1 [KO:K13240] [EC:]
4843  NOS2; nitric oxide synthase 2 [KO:K13241] [EC:]
4846  NOS3; nitric oxide synthase 3 [KO:K13242] [EC:]
5581  PRKCE; protein kinase C epsilon [KO:K18050] [EC:]
6548  SLC9A1; solute carrier family 9 member A1 [KO:K05742]
6546  SLC8A1; solute carrier family 8 member A1 [KO:K05849]
6543  SLC8A2; solute carrier family 8 member A2 [KO:K05849]
6547  SLC8A3; solute carrier family 8 member A3 [KO:K05849]
4638  MYLK; myosin light chain kinase [KO:K00907] [EC:]
85366  MYLK2; myosin light chain kinase 2 [KO:K00907] [EC:]
91807  MYLK3; myosin light chain kinase 3 [KO:K00907] [EC:]
340156  MYLK4; myosin light chain kinase family member 4 [KO:K00907] [EC:]
4633  MYL2; myosin light chain 2 [KO:K10351]
4634  MYL3; myosin light chain 3 [KO:K12749]
4635  MYL4; myosin light chain 4 [KO:K12750]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
6237  RRAS; RAS related [KO:K07829]
22800  RRAS2; RAS related 2 [KO:K07830]
22808  MRAS; muscle RAS oncogene homolog [KO:K07831]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:]
6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:]
6194  RPS6; ribosomal protein S6 [KO:K02991]
5294  PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K21289] [EC:]
23533  PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K21290]
146850  PIK3R6; phosphoinositide-3-kinase regulatory subunit 6 [KO:K21290]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:]
1958  EGR1; early growth response 1 [KO:K09203]
6696  SPP1; secreted phosphoprotein 1 [KO:K06250]
182  JAG1; jagged canonical Notch ligand 1 [KO:K06052]
4854  NOTCH3; notch receptor 3 [KO:K20995]
595  CCND1; cyclin D1 [KO:K04503]
5140  PDE3B; phosphodiesterase 3B [KO:K13296] [EC:]
5289  PIK3C3; phosphatidylinositol 3-kinase catalytic subunit type 3 [KO:K00914] [EC:]
30849  PIK3R4; phosphoinositide-3-kinase regulatory subunit 4 [KO:K08333] [EC:]
8678  BECN1; beclin 1 [KO:K08334]
441925  BECN2; beclin 2 [KO:K08334]
440738  MAP1LC3C; microtubule associated protein 1 light chain 3 gamma [KO:K10435]
81631  MAP1LC3B; microtubule associated protein 1 light chain 3 beta [KO:K10435]
84557  MAP1LC3A; microtubule associated protein 1 light chain 3 alpha [KO:K10435]
643246  MAP1LC3B2; microtubule associated protein 1 light chain 3 beta 2 [KO:K10435]
5562  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:]
5563  PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:]
5564  PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
5565  PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
5571  PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
53632  PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
51422  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
5346  PLIN1; perilipin 1 [KO:K08768]
10891  PPARGC1A; PPARG coactivator 1 alpha [KO:K07202]
7350  UCP1; uncoupling protein 1 [KO:K08769]
4899  NRF1; nuclear respiratory factor 1 [KO:K11831]
7019  TFAM; transcription factor A, mitochondrial [KO:K11830]
10365  KLF2; KLF transcription factor 2 [KO:K17845]
8877  SPHK1; sphingosine kinase 1 [KO:K04718] [EC:]
56848  SPHK2; sphingosine kinase 2 [KO:K04718] [EC:]
10672  GNA13; G protein subunit alpha 13 [KO:K04639]
814  CAMK4; calcium/calmodulin dependent protein kinase IV [KO:K05869] [EC:]
9759  HDAC4; histone deacetylase 4 [KO:K11406] [EC:]
10014  HDAC5; histone deacetylase 5 [KO:K11406] [EC:]
4205  MEF2A; myocyte enhancer factor 2A [KO:K09260]
4207  BORCS8-MEF2B; BORCS8-MEF2B readthrough [KO:K09261]
100271849  MEF2B; myocyte enhancer factor 2B [KO:K09261]
4208  MEF2C; myocyte enhancer factor 2C [KO:K04454]
4209  MEF2D; myocyte enhancer factor 2D [KO:K09262]
7046  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:]
4087  SMAD2; SMAD family member 2 [KO:K04500]
4088  SMAD3; SMAD family member 3 [KO:K23605]
4089  SMAD4; SMAD family member 4 [KO:K04501]
59  ACTA2; actin alpha 2, smooth muscle [KO:K12313]
999  CDH1; cadherin 1 [KO:K05689]
1490  CCN2; cellular communication network factor 2 [KO:K06827]
185  AGTR1; angiotensin II receptor type 1 [KO:K04166]
5054  SERPINE1; serpin family E member 1 [KO:K03982]
5327  PLAT; plasminogen activator, tissue type [KO:K01343] [EC:]
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
Yang P, Maguire JJ, Davenport AP
Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system.
Trends Pharmacol Sci 36:560-7 (2015)
Andersen CU, Hilberg O, Mellemkjaer S, Nielsen-Kudsk JE, Simonsen U
Apelin and pulmonary hypertension.
Pulm Circ 1:334-46 (2011)
Chapman NA, Dupre DJ, Rainey JK
The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR.
Biochem Cell Biol 92:431-40 (2014)
Japp AG, Newby DE
The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential.
Biochem Pharmacol 75:1882-92 (2008)
Folino A, Montarolo PG, Samaja M, Rastaldo R
Effects of apelin on the cardiovascular system.
Heart Fail Rev 20:505-18 (2015)
O'Carroll AM, Lolait SJ, Harris LE, Pope GR
The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis.
J Endocrinol 219:R13-35 (2013)
Liu QF, Yu HW, You L, Liu MX, Li KY, Tao GZ
Apelin-13-induced proliferation and migration induced of rat vascular smooth muscle cells is mediated by the upregulation of Egr-1.
Biochem Biophys Res Commun 439:235-40 (2013)
Novakova V, Sandhu GS, Dragomir-Daescu D, Klabusay M
Apelinergic system in endothelial cells and its role in angiogenesis in myocardial ischemia.
Vascul Pharmacol 76:1-10 (2016)
Castan-Laurell I, Dray C, Attane C, Duparc T, Knauf C, Valet P
Apelin, diabetes, and obesity.
Endocrine 40:1-9 (2011)
Li L, Li L, Xie F, Zhang Z, Guo Y, Tang G, Lv D, Lu Q, Chen L, Li J
Jagged-1/Notch3 signaling transduction pathway is involved in apelin-13-induced vascular smooth muscle cells proliferation.
Acta Biochim Biophys Sin (Shanghai) 45:875-81 (2013)
Wu D, He L, Chen L
Apelin/APJ system: a promising therapy target for hypertension.
Mol Biol Rep 41:6691-703 (2014)
Liu C, Su T, Li F, Li L, Qin X, Pan W, Feng F, Chen F, Liao D, Chen L
PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin-13.
Acta Biochim Biophys Sin (Shanghai) 42:396-402 (2010)
Xie F, Liu W, Feng F, Li X, He L, Lv D, Qin X, Li L, Li L, Chen L
Apelin-13 promotes cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy.
Acta Biochim Biophys Sin (Shanghai) 47:969-80 (2015)
Lu L, Wu D, Li L, Chen L
Apelin/APJ system: A bifunctional target for cardiac hypertrophy.
Int J Cardiol 230:164-170 (2017)
Carmen GY, Victor SM
Signalling mechanisms regulating lipolysis.
Cell Signal 18:401-8 (2006)
Hu H, He L, Li L, Chen L
Apelin/APJ system as a therapeutic target in diabetes and its complications.
Mol Genet Metab 119:20-7 (2016)
Bertrand C, Valet P, Castan-Laurell I
Apelin and energy metabolism.
Front Physiol 6:115 (2015)
Yao F, Lv YC, Zhang M, Xie W, Tan YL, Gong D, Cheng HP, Liu D, Li L, Liu XY, Zheng XL, Tang CK
Apelin-13 impedes foam cell formation by activating Class III PI3K/Beclin-1-mediated autophagic pathway.
Biochem Biophys Res Commun 466:637-43 (2015)
Than A, Cheng Y, Foh LC, Leow MK, Lim SC, Chuah YJ, Kang Y, Chen P
Apelin inhibits adipogenesis and lipolysis through distinct molecular pathways.
Mol Cell Endocrinol 362:227-41 (2012)
Yu XH, Tang ZB, Liu LJ, Qian H, Tang SL, Zhang DW, Tian GP, Tang CK
Apelin and its receptor APJ in cardiovascular diseases.
Clin Chim Acta 428:1-8 (2014)
Than A, He HL, Chua SH, Xu D, Sun L, Leow MK, Chen P
Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes.
J Biol Chem 290:14679-91 (2015)
Fu J, Li Z, Zhang H, Mao Y, Wang A, Wang X, Zou Z, Zhang X
Molecular pathways regulating the formation of brown-like adipocytes in white adipose tissue.
Diabetes Metab Res Rev 31:433-52 (2015)
Aharoni-Simon M, Hann-Obercyger M, Pen S, Madar Z, Tirosh O
Fatty liver is associated with impaired activity of PPARgamma-coactivator 1alpha (PGC1alpha) and mitochondrial biogenesis in mice.
Lab Invest 91:1018-28 (2011)
McLean DL, Kim J, Kang Y, Shi H, Atkins GB, Jain MK, Chun HJ
Apelin/APJ signaling is a critical regulator of statin effects in vascular endothelial cells--brief report.
Arterioscler Thromb Vasc Biol 32:2640-3 (2012)
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
Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1.
Eur Heart J 33:2360-9 (2012)
Huang S, Chen L, Lu L, Li L
The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis.
Clin Chim Acta 456:81-8 (2016)
Liu G, Han J, Profirovic J, Strekalova E, Voyno-Yasenetskaya TA
Galpha13 regulates MEF2-dependent gene transcription in endothelial cells: role in angiogenesis.
Angiogenesis 12:1-15 (2009)
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
Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development.
Circ Res 113:22-31 (2013)
Wang LY, Diao ZL, Zhang DL, Zheng JF, Zhang QD, Ding JX, Liu WH
The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis.
Amino Acids 46:2693-704 (2014)
Zhou Y, Deng L, Zhao D, Chen L, Yao Z, Guo X, Liu X, Lv L, Leng B, Xu W, Qiao G, Shan H
MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin-13.
J Cell Mol Med 20:495-505 (2016)
Zhong JC, Zhang ZZ, Wang W, McKinnie SM, Vederas JC, Oudit GY
Targeting the apelin pathway as a novel therapeutic approach for cardiovascular diseases.
Biochim Biophys Acta 1863:1942-1950 (2017)
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04140  Autophagy - animal
hsa04150  mTOR signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04152  AMPK signaling pathway
hsa04270  Vascular smooth muscle contraction
hsa04530  Tight junction
hsa04923  Regulation of lipolysis in adipocytes
KO pathway

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