KEGG   PATHWAY: bta04935
Entry
bta04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Bos taurus (cow)
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
bta04935  Growth hormone synthesis, secretion and action
bta04935

Organism
Bos taurus (cow) [GN:bta]
Gene
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100138040  SOS2; son of sevenless homolog 2 [KO:K03099]
100139219  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100298939  HRAS; GTPase HRas isoform 1 [KO:K02833]
100300012  IRS2; insulin receptor substrate 2 [KO:K07187]
100337091  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
100337204  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S isoform X1 [KO:K04857]
100847184  [KO:K02833]
101905399  [KO:K04368] [EC:2.7.12.2]
107131319  SSTR1; somatostatin receptor type 1 [KO:K04217]
107131843  IRS3; insulin receptor substrate 1 isoform X1 [KO:K17445]
112446776  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
280795  FOS; protein c-Fos [KO:K04379]
280804  GH1; somatotropin precursor [KO:K05438]
280805  GHR; growth hormone receptor precursor [KO:K05080]
280932  SST; somatostatin precursor [KO:K05237]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
281191  GHRH; somatoliberin precursor [KO:K05260]
281192  GHRL; appetite-regulating hormone precursor [KO:K05254]
281239  IGF1; insulin-like growth factor I preproprotein [KO:K05459]
281601  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
281603  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
281713  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
281715  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
281782  GHRHR; growth hormone-releasing hormone receptor precursor [KO:K04584]
281788  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
281790  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
281791  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
281793  GNAS; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
281878  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
281879  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
281985  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
281987  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
282001  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
282002  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
282081  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
282083  SSTR2; somatostatin receptor type 2 [KO:K04218]
282261  IGFBP3; insulin-like growth factor-binding protein 3 precursor [KO:K10138]
282306  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
282307  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
282308  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
282315  POU1F1; pituitary-specific positive transcription factor 1 [KO:K09363]
282322  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
282323  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
282325  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
282375  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
282376  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
286865  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
286883  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
287026  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
317697  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
327672  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
338437  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
408013  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
408015  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
504531  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
505453  CREBBP; CREB-binding protein [KO:K04498] [EC:2.3.1.48]
505740  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
506270  PTK2; PTK2 protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
506322  NRAS; GTPase NRas [KO:K07828]
507196  SHC1; SHC-transforming protein 1 isoform b [KO:K06279]
508541  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
508888  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
509107  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
509779  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
509827  ATF2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
509936  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
510344  SSTR5; somatostatin receptor type 5 [KO:K04221]
510434  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
510708  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
510814  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
512696  SHC3; SHC-transforming protein 3 isoform X3 [KO:K17448]
512841  CRK; adapter molecule crk [KO:K04438]
512943  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
513010  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
513105  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
513928  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
514203  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
514246  JUNB; transcription factor JunB [KO:K09028]
514607  IRS4; insulin receptor substrate 4 [KO:K17446]
515669  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
516039  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
517948  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
518180  CRKL; crk-like protein [KO:K04438]
518585  SSTR3; somatostatin receptor type 3 [KO:K04219]
518795  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
521196  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
521844  ADCY10; adenylate cyclase type 10 isoform X1 [KO:K11265] [EC:4.6.1.1]
523962  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
524734  SHC4; SHC-transforming protein 4 [KO:K17449]
525246  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
525482  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
526469  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
527550  BCAR1; breast cancer anti-estrogen resistance protein 1 [KO:K05726]
529566  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X5 [KO:K09048]
531391  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
531747  [KO:K11265] [EC:4.6.1.1]
532494  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit precursor [KO:K17256]
533199  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
533455  SHC2; SHC-transforming protein 2 [KO:K17447]
534125  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
534129  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
534492  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
535017  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
535298  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
535327  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
535603  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
536654  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
537631  MAPK10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
537682  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
538598  IRS1; insulin receptor substrate 1 [KO:K16172]
539521  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
539941  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
541140  KRAS; GTPase KRas [KO:K07827]
618906  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
781188  MRAP2; melanocortin-2 receptor accessory protein 2 [KO:K25968]
785086  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
788151  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
790875  GSK3B; glycogen synthase kinase-3 beta [KO:K03083] [EC:2.7.11.26]
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
bta04010  MAPK signaling pathway
bta04020  Calcium signaling pathway
bta04024  cAMP signaling pathway
bta04630  JAK-STAT signaling pathway
KO pathway
ko04935   

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