KEGG   PATHWAY: oro04935
Entry
oro04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Odobenus rosmarus divergens (Pacific walrus)
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
oro04935  Growth hormone synthesis, secretion and action
oro04935

Organism
Odobenus rosmarus divergens (Pacific walrus) [GN:oro]
Gene
101368094  GHRH; somatoliberin [KO:K05260]
101379693  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
101364060  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
105757053  neuroendocrine secretory protein 55 [KO:K04632]
101379158  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101365382  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101368682  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101374313  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
101380824  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101373816  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
101377421  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101370350  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101364108  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101363792  adenylate cyclase type 10-like [KO:K11265] [EC:4.6.1.1]
101379936  ADCY10; adenylate cyclase type 10 isoform X2 [KO:K11265] [EC:4.6.1.1]
101378609  SST; somatostatin [KO:K05237]
101379420  SSTR1; somatostatin receptor type 1 [KO:K04217]
101368246  SSTR2; somatostatin receptor type 2 [KO:K04218]
101386415  SSTR3; somatostatin receptor type 3 [KO:K04219]
101383018  SSTR5; somatostatin receptor type 5 [KO:K04221]
101376186  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
101367568  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101367936  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
101367408  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
101383001  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101383024  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101374034  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101368122  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101383806  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101385783  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101376293  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
101381943  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
101385675  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101384862  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
101381436  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
101362815  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
101386879  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
101379566  POU1F1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
101366773  FOS; proto-oncogene c-Fos isoform X1 [KO:K04379]
101371706  somatotropin isoform X1 [KO:K05438]
101369258  GHRL; appetite-regulating hormone isoform X1 [KO:K05254]
101370855  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
101386306  MRAP2; melanocortin-2 receptor accessory protein 2 [KO:K25968]
101384596  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101385358  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
101379806  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
101375710  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
101386162  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X2 [KO:K05858] [EC:3.1.4.11]
101386750  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101386060  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101380879  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101363254  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101367743  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
101377380  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
101380808  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X2 [KO:K04960]
101385947  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
101365624  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
101383514  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
101364481  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
101370443  GHR; growth hormone receptor [KO:K05080]
101375007  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
101380728  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
101378505  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
101373821  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
101384118  SHC2; SHC-transforming protein 2 [KO:K17447]
101375500  SHC3; SHC-transforming protein 3 [KO:K17448]
101375729  SHC4; SHC-transforming protein 4 [KO:K17449]
101362094  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
101385114  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101369947  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
101367134  GTPase HRas-like [KO:K02833]
101372786  HRAS; GTPase HRas isoform X1 [KO:K02833]
101370458  KRAS; GTPase KRas isoform X2 [KO:K07827]
101363525  NRAS; GTPase NRas [KO:K07828]
101372149  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
101365373  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
101376586  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101372573  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101382213  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101378785  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
101373587  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
101372719  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
101372217  STAT5B; signal transducer and activator of transcription 5B isoform X2 [KO:K11224]
101367978  IRS1; insulin receptor substrate 1 [KO:K16172]
101381397  IRS2; insulin receptor substrate 2 [KO:K07187]
101378833  insulin receptor substrate 2-like [KO:K17445]
101371781  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
101374787  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
101370100  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101371800  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101370689  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101385241  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101385267  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
101383166  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101382320  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101374757  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101363844  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101365718  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
101386334  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
101371082  JUNB; transcription factor jun-B [KO:K09028]
101376722  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101373719  SOCS2; LOW QUALITY PROTEIN: suppressor of cytokine signaling 2 [KO:K04695]
101364487  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101366100  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
101376941  IGFBP3; insulin-like growth factor-binding protein 3 isoform X1 [KO:K10138]
101371010  PTK2; focal adhesion kinase 1 isoform X1 [KO:K05725] [EC:2.7.10.2]
101364349  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
101369015  CRKL; crk-like protein [KO:K04438]
101384062  CRK; adapter molecule crk isoform X1 [KO:K04438]
101366511  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
101378651  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
101386473  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X2 [KO:K04430] [EC:2.7.12.2]
101382167  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
101367488  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101374143  MAPK8; mitogen-activated protein kinase 8 isoform X3 [KO:K04440] [EC:2.7.11.24]
101376185  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
101377143  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
101377430  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101382259  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
101382558  MAPK12; mitogen-activated protein kinase 12 [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
oro04010  MAPK signaling pathway
oro04020  Calcium signaling pathway
oro04024  cAMP signaling pathway
oro04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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