KEGG   PATHWAY: ecb04935
Entry
ecb04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Equus caballus (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
ecb04935  Growth hormone synthesis, secretion and action
ecb04935

Organism
Equus caballus (horse) [GN:ecb]
Gene
111769907  GHRH; somatoliberin [KO:K05260]
100069933  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
100056464  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100050675  neuroendocrine secretory protein 55 [KO:K04632]
100065563  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100071337  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
100055961  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100054305  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100070498  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100051295  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
100058891  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100057796  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100066046  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100066125  adenylate cyclase type 10 isoform X1 [KO:K11265] [EC:4.6.1.1]
100056933  ADCY10; adenylate cyclase type 10 isoform X1 [KO:K11265] [EC:4.6.1.1]
100059610  SST; somatostatin [KO:K05237]
100060276  SSTR1; somatostatin receptor type 1 [KO:K04217]
100052744  SSTR2; somatostatin receptor type 2 [KO:K04218]
100069706  SSTR3; somatostatin receptor type 3 [KO:K04219]
100067398  SSTR5; somatostatin receptor type 5 [KO:K04221]
100055673  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100062085  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100058238  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100052828  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100064302  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X3 [KO:K04345] [EC:2.7.11.11]
100066388  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
100053304  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100070334  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100062307  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100064828  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100057002  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100067794  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100063153  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100054803  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100059348  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
100055626  EP300; histone acetyltransferase p300 isoform X2 [KO:K04498] [EC:2.3.1.48]
100069613  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
100054339  POU1F1; pituitary-specific positive transcription factor 1 [KO:K09363]
100051632  FOS; proto-oncogene c-Fos [KO:K04379]
100034180  GH1; somatotropin precursor [KO:K05438]
100058008  GHRL; appetite-regulating hormone [KO:K05254]
100057865  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
100065482  MRAP2; melanocortin-2 receptor accessory protein 2 isoform X1 [KO:K25968]
100063136  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100067327  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100057315  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
100051558  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100055407  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
100051485  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100063318  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100069215  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100062549  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100052808  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
100064557  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
100053019  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
100034092  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100049924  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
100051186  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100062861  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
100053020  GHR; growth hormone receptor isoform X2 [KO:K05080]
100051487  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
100070545  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X3 [KO:K01116] [EC:3.1.4.11]
100055670  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X2 [KO:K05859] [EC:3.1.4.11]
100063053  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100146209  SHC2; SHC-transforming protein 2 [KO:K17447]
100061926  SHC3; SHC-transforming protein 3 [KO:K17448]
100055699  SHC4; SHC-transforming protein 4 [KO:K17449]
100051866  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100053889  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100066282  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100055481  HRAS; GTPase HRas isoform X1 [KO:K02833]
100064473  KRAS; GTPase KRas isoform X1 [KO:K07827]
100051785  LOW QUALITY PROTEIN: GTPase KRas-like [KO:K07827]
100059469  NRAS; GTPase NRas [KO:K07828]
100051110  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100065996  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:2.7.12.2]
100063190  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100057701  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
100066173  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100069633  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100034011  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
100052904  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
100052954  signal transducer and activator of transcription 5B isoform X3 [KO:K11224]
100061987  IRS1; insulin receptor substrate 1 [KO:K16172]
100146249  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
100069009  insulin receptor substrate 1 isoform X1 [KO:K17445]
100059954  IRS4; insulin receptor substrate 4 [KO:K17446]
100052122  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100050227  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
100146348  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100051623  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100058141  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100051753  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100064671  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100054961  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100061130  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100051341  MTOR; serine/threonine-protein kinase mTOR isoform X3 [KO:K07203] [EC:2.7.11.1]
100061033  GSK3B; glycogen synthase kinase-3 beta isoform X6 [KO:K03083] [EC:2.7.11.26]
100034198  IGF1; insulin-like growth factor I precursor [KO:K05459]
100146801  JUNB; transcription factor jun-B [KO:K09028]
102148488  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
100051952  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100050730  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
111767589  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
100034155  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
100058245  PTK2; focal adhesion kinase 1 isoform X12 [KO:K05725] [EC:2.7.10.2]
100068908  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
100072356  CRK; adapter molecule crk isoform X1 [KO:K04438]
100050855  CRKL; crk-like protein [KO:K04438]
100061688  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
100053481  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
100073094  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
100053056  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform X1 [KO:K04433] [EC:2.7.12.2]
100052608  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100057961  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100051798  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100056278  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
100056239  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100063532  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
106782258  MAPK13; mitogen-activated protein kinase 13 [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
ecb04010  MAPK signaling pathway
ecb04020  Calcium signaling pathway
ecb04024  cAMP signaling pathway
ecb04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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