KEGG   PATHWAY: hsa04935
Entry
hsa04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Homo sapiens (human)
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
hsa04935  Growth hormone synthesis, secretion and action
hsa04935

Network
  Element
N00907  GH-Jak-STAT signaling pathway
N00910  GHRHR-PKA-GH signaling pathway
Drug
D02250  Octreotide acetate (JAN)
D02691  Somatropin (USP/INN)
D03297  Mecasermin (USAN/INN)
D04666  Lanreotide acetate (JAN/USAN)
D05394  Pegvisomant (USAN/INN)
D06495  Octreotide acetate (USP)
D09015  Tesamorelin acetate (USAN)
D10497  Pasireotide diaspartate
D10566  Pasireotide pamoate (JAN)
D10990  Somatrogon (USAN/INN)
D11033  Lutetium (177Lu) oxodotreotide (INN)
D11194  Somapacitan (USAN/INN)
D11486  Lonapegsomatropin (USAN/INN)
D11651  Edotreotide gallium Ga-68
D11882  Copper Cu 64 dotatate
D12431  Lutetium Lu177 edotreotide (USAN)
D12477  Paltusotine (USAN/INN)
D12478  Paltusotine hydrochloride (USAN)
D12907  Actinium Ac 225 dotatate (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
2691  GHRH; growth hormone releasing hormone [KO:K05260]
2692  GHRHR; growth hormone releasing hormone receptor [KO:K04584]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
55811  ADCY10; adenylate cyclase 10 [KO:K11265] [EC:4.6.1.1]
6750  SST; somatostatin [KO:K05237]
6751  SSTR1; somatostatin receptor 1 [KO:K04217]
6752  SSTR2; somatostatin receptor 2 [KO:K04218]
6753  SSTR3; somatostatin receptor 3 [KO:K04219]
6755  SSTR5; somatostatin receptor 5 [KO:K04221]
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]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
468  ATF4; activating transcription factor 4 [KO:K04374]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
1387  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
5449  POU1F1; POU class 1 homeobox 1 [KO:K09363]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
2688  GH1; growth hormone 1 [KO:K05438]
2689  GH2; growth hormone 2 [KO:K05438]
1442  CSH1; chorionic somatomammotropin hormone 1 [KO:K05438]
1443  CSH2; chorionic somatomammotropin hormone 2 [KO:K05438]
51738  GHRL; ghrelin and obestatin prepropeptide [KO:K05254]
2693  GHSR; growth hormone secretagogue receptor [KO:K04284]
112609  MRAP2; melanocortin 2 receptor accessory protein 2 [KO:K25968]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
2767  GNA11; G protein subunit alpha 11 [KO:K04635]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
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]
779  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
778  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
2690  GHR; growth hormone receptor [KO:K05080]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
5335  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5336  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
6464  SHC1; SHC adaptor protein 1 [KO:K06279]
25759  SHC2; SHC adaptor protein 2 [KO:K17447]
53358  SHC3; SHC adaptor protein 3 [KO:K17448]
399694  SHC4; SHC adaptor protein 4 [KO:K17449]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
6774  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
6776  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
6777  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
3667  IRS1; insulin receptor substrate 1 [KO:K16172]
8660  IRS2; insulin receptor substrate 2 [KO:K07187]
8471  IRS4; insulin receptor substrate 4 [KO:K17446]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
3726  JUNB; JunB proto-oncogene, AP-1 transcription factor subunit [KO:K09028]
8651  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
8835  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
9021  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
3483  IGFALS; insulin like growth factor binding protein acid labile subunit [KO:K17256]
3486  IGFBP3; insulin like growth factor binding protein 3 [KO:K10138]
5747  PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
9564  BCAR1; BCAR1 scaffold protein, Cas family member [KO:K05726]
1398  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
1399  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
4214  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
6416  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [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
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04024  cAMP signaling pathway
hsa04630  JAK-STAT signaling pathway
KO pathway
ko04935   
LinkDB

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