KEGG   PATHWAY: epz04935
Entry
epz04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Equus przewalskii (Przewalski's horse)
Description
Growth hormone (GH) is a peptide hormone secreted from the anterior pituitary and plays a critical role in cell growth, development, and metabolism throughout the body. GH secretion occurs episodically and is primarily under the control of two hypothalamic neuroendocrine hormones: GH-releasing hormone (GHRH), which stimulates GH secretion, and somatostatin, which inhibits GH secretion. GHRH interacts with a G protein-coupled receptor (GHRHR) in somatotroph cells to activate the cAMP signaling pathway, which leads to increased GH mRNA transcription and release. Once released into the circulation, GH binds to cell-surface GHR in target tissues such as liver, muscle, bone, and adipose tissue. Binding leads to activation of JAK2 that in turn triggers an array of signaling cascade including Raf-MEK-ERK, PI3K-Akt, and STAT5. ERK, Akt, and STAT5 all promote growth via the synthesis and secretion of IGF-1.
Class
Organismal Systems; Endocrine system
Pathway map
epz04935  Growth hormone synthesis, secretion and action
epz04935

Organism
Equus przewalskii (Przewalski's horse) [GN:epz]
Gene
103560908  GHRH; growth hormone releasing hormone [KO:K05260]
103559363  GHRHR; growth hormone releasing hormone receptor [KO:K04584]
103565402  guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
103547036  neuroendocrine secretory protein 55 [KO:K04632]
103550430  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
103562505  adenylate cyclase type 2-like [KO:K08042] [EC:4.6.1.1]
103547823  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
103561050  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
103563830  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
103563634  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
103556685  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
103565019  adenylate cyclase type 8-like [KO:K08048] [EC:4.6.1.1]
103567623  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
103553014  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
103551549  ADCY10; adenylate cyclase 10, soluble [KO:K11265] [EC:4.6.1.1]
103555495  adenylate cyclase type 10-like [KO:K11265] [EC:4.6.1.1]
103557268  SST; somatostatin [KO:K05237]
103551694  SSTR1; somatostatin receptor 1 [KO:K04217]
103547403  SSTR2; somatostatin receptor 2 [KO:K04218]
103564460  SSTR3; somatostatin receptor 3 [KO:K04219]
103540984  SSTR5; somatostatin receptor 5 [KO:K04221]
103552141  guanine nucleotide-binding protein G(i) subunit alpha-1-like [KO:K04630]
103553052  GNAI3; G protein subunit alpha i3 [KO:K04630]
103557343  GNAI2; G protein subunit alpha i2 [KO:K04630]
103557289  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103565953  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
103548908  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
103553756  ATF2; activating transcription factor 2 [KO:K04450]
103565289  ATF4; activating transcription factor 4 [KO:K04374]
103566499  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
103560297  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
103564266  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
103555399  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
103549839  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
103563297  ATF6B; activating transcription factor 6 beta [KO:K09049]
103553025  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
103556116  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
103540882  POU1F1; POU class 1 homeobox 1 [KO:K09363]
103548618  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
103549756  somatotropin [KO:K05438]
103561465  GHRL; ghrelin and obestatin prepropeptide [KO:K05254]
103546357  GHSR; growth hormone secretagogue receptor [KO:K04284]
103546983  MRAP2; melanocortin 2 receptor accessory protein 2 [KO:K25968]
103553450  GNAQ; G protein subunit alpha q [KO:K04634]
103543382  guanine nucleotide-binding protein subunit alpha-11-like [KO:K04635]
103562440  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
103559733  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
103561633  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
103542193  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
103558165  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
103556196  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
103550297  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
103546630  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
103548182  inositol 1,4,5-trisphosphate receptor type 2-like [KO:K04959]
103564724  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
103565109  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
103560754  voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
103543955  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
103553842  GHR; growth hormone receptor [KO:K05080]
103554269  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
103562208  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
103558212  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
103552865  SHC1; SHC adaptor protein 1 [KO:K06279]
103542441  SHC2; SHC adaptor protein 2 [KO:K17447]
103552516  SHC3; SHC adaptor protein 3 [KO:K17448]
103551857  SHC4; SHC adaptor protein 4 [KO:K17449]
103546580  GRB2; growth factor receptor bound protein 2 [KO:K04364]
103553088  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
103556123  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
103567332  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
103546629  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
103552675  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
103554541  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
103549630  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103543290  dual specificity mitogen-activated protein kinase kinase 2-like [KO:K04369] [EC:2.7.12.2]
103547261  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103562408  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103548655  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
103550364  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
103550390  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
103550391  signal transducer and activator of transcription 5B [KO:K11224]
103547143  IRS1; insulin receptor substrate 1 [KO:K16172]
103555632  insulin receptor substrate 1-like [KO:K17445]
103545515  IRS4; insulin receptor substrate 4 [KO:K17446]
103548220  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103551868  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103561550  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103549076  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
103554655  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform-like [KO:K00922] [EC:2.7.1.153]
103552150  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
103560497  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
103540249  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
103555421  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
103552237  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
103547424  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
103549360  IGF1; insulin like growth factor 1 [KO:K05459]
103540637  JUNB; JunB proto-oncogene, AP-1 transcription factor subunit [KO:K09028]
103564583  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
103554055  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
103540033  IGFALS; insulin like growth factor binding protein acid labile subunit [KO:K17256]
103550432  IGFBP3; insulin like growth factor binding protein 3 [KO:K10138]
103561848  PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
103553038  BCAR1; BCAR1, Cas family scaffolding protein [KO:K05726]
103547531  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
103543614  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
103548212  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
103563092  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
103567795  dual specificity mitogen-activated protein kinase kinase 4-like [KO:K04430] [EC:2.7.12.2]
103564566  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
103549414  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
103553980  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
103567629  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
103565534  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
103563198  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
103559485  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
103559491  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
  Authors
Nishad R, Mukhi D, Menon R K, Pasupulati A.
  Title
Growth Hormone and Metabolic Homeostasis
  Journal
Eur Med J 6:78-87 (2018)
Reference
PMID:30775002
  Authors
Lu M, Flanagan JU, Langley RJ, Hay MP, Perry JK
  Title
Targeting growth hormone function: strategies and therapeutic applications.
  Journal
Signal Transduct Target Ther 4:3 (2019)
DOI:10.1038/s41392-019-0036-y
Reference
PMID:8874495
  Authors
Argetsinger LS, Carter-Su C
  Title
Mechanism of signaling by growth hormone receptor.
  Journal
Physiol Rev 76:1089-107 (1996)
DOI:10.1152/physrev.1996.76.4.1089
Reference
PMID:8815791
  Authors
Carter-Su C, Schwartz J, Smit LS
  Title
Molecular mechanism of growth hormone action.
  Journal
Annu Rev Physiol 58:187-207 (1996)
DOI:10.1146/annurev.ph.58.030196.001155
Reference
PMID:10912517
  Authors
Carter-Su C, Rui L, Herrington J
  Title
Role of the tyrosine kinase JAK2 in signal transduction by growth hormone.
  Journal
Pediatr Nephrol 14:550-7 (2000)
DOI:10.1007/s004670000366
Reference
PMID:29487568
  Authors
Dehkhoda F, Lee CMM, Medina J, Brooks AJ
  Title
The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects.
  Journal
Front Endocrinol (Lausanne) 9:35 (2018)
DOI:10.3389/fendo.2018.00035
Reference
PMID:26421979
  Authors
Carter-Su C, Schwartz J, Argetsinger LS
  Title
Growth hormone signaling pathways.
  Journal
Growth Horm IGF Res 28:11-5 (2016)
DOI:10.1016/j.ghir.2015.09.002
Reference
PMID:28435436
  Authors
Berryman DE, Henry B, Hjortebjerg R, List EO, Kopchick JJ
  Title
Developments in our understanding of the effects of growth hormone on white adipose tissue from mice: implications to the clinic.
  Journal
Expert Rev Endocrinol Metab 11:197-207 (2016)
DOI:10.1586/17446651.2016.1147950
Reference
PMID:9837978
  Authors
Zhu T, Goh EL, LeRoith D, Lobie PE
  Title
Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII. Resultant activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK).
  Journal
J Biol Chem 273:33864-75 (1998)
DOI:10.1074/jbc.273.50.33864
Reference
  Authors
Choi S (ed).
  Title
Encyclopedia of Signaling Molecules
  Journal
Springer International Publishing
DOI:10.1007/978-1-4614-6438-9_101674-1
Reference
PMID:11997217
  Authors
Gracia-Navarro F, Castano JP, Malagon MM, Sanchez-Hormigo A, Luque RM, Hickey GJ, Peinado JR, Delgado E, Martinez-Fuentes AJ
  Title
Research progress in the stimulatory inputs regulating growth hormone (GH) secretion.
  Journal
Comp Biochem Physiol B Biochem Mol Biol 132:141-50 (2002)
DOI:10.1016/s1096-4959(01)00544-9
Reference
PMID:9167959
  Authors
Bertherat J
  Title
Nuclear effects of the cAMP pathway activation in somatotrophs.
  Journal
Horm Res 47:245-50 (1997)
DOI:10.1159/000185471
Reference
PMID:8625613
  Authors
Tuggle CK, Trenkle A
  Title
Control of growth hormone synthesis.
  Journal
Domest Anim Endocrinol 13:1-33 (1996)
DOI:10.1016/0739-7240(95)00059-3
Reference
PMID:10525051
  Authors
Cohen LE, Hashimoto Y, Zanger K, Wondisford F, Radovick S
  Title
CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression.
  Journal
J Clin Invest 104:1123-30 (1999)
DOI:10.1172/JCI7308
Reference
PMID:25302229
  Authors
Khatib N, Gaidhane S, Gaidhane AM, Khatib M, Simkhada P, Gode D, Zahiruddin QS
  Title
Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.
  Journal
J Clin Diagn Res 8:MC13-7 (2014)
DOI:10.7860/JCDR/2014/9863.4767
Reference
PMID:16628271
  Authors
Lengyel AM
  Title
From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion.
  Journal
Arq Bras Endocrinol Metabol 50:17-24 (2006)
DOI:10.1590/s0004-27302006000100004
Reference
PMID:15927771
  Authors
Anderson LL, Jeftinija S, Scanes CG, Stromer MH, Lee JS, Jeftinija K, Glavaski-Joksimovic A
  Title
Physiology of ghrelin and related peptides.
  Journal
Domest Anim Endocrinol 29:111-44 (2005)
DOI:10.1016/j.domaniend.2005.02.033
Reference
PMID:14610293
  Authors
Camina JP, Carreira MC, Micic D, Pombo M, Kelestimur F, Dieguez C, Casanueva FF
  Title
Regulation of ghrelin secretion and action.
  Journal
Endocrine 22:5-12 (2003)
DOI:10.1385/ENDO:22:1:5
Reference
PMID:22243899
  Authors
Yang SK, Steyn F, Chen C
  Title
Influence of membrane ion channel in pituitary somatotrophs by hypothalamic regulators.
  Journal
Cell Calcium 51:231-9 (2012)
DOI:10.1016/j.ceca.2011.12.005
Reference
PMID:19884662
  Authors
Melmed S
  Title
Acromegaly pathogenesis and treatment.
  Journal
J Clin Invest 119:3189-202 (2009)
DOI:10.1172/JCI39375
Reference
PMID:31911434
  Authors
Rouault AAJ, Rosselli-Murai LK, Hernandez CC, Gimenez LE, Tall GG, Sebag JA
  Title
The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a.
  Journal
Sci Signal 13:eaax4569 (2020)
DOI:10.1126/scisignal.aax4569
Related
pathway
epz04010  MAPK signaling pathway
epz04020  Calcium signaling pathway
epz04024  cAMP signaling pathway
epz04630  JAK-STAT signaling pathway
KO pathway
ko04935   
LinkDB

DBGET integrated database retrieval system