KEGG   PATHWAY: pon04935
Entry
pon04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Pongo abelii (Sumatran orangutan)
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
pon04935  Growth hormone synthesis, secretion and action
pon04935

Organism
Pongo abelii (Sumatran orangutan) [GN:pon]
Gene
100935729  GHRH; somatoliberin [KO:K05260]
100446338  GHRHR; growth hormone-releasing hormone receptor isoform X1 [KO:K04584]
100442753  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X3 [KO:K04632]
103888841  neuroendocrine secretory protein 55 [KO:K04632]
100449504  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
100445431  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100431221  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
100460806  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100454138  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
100438178  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100436577  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
100461383  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
103889530  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100459701  ADCY10; adenylate cyclase type 10 isoform X1 [KO:K11265] [EC:4.6.1.1]
100440911  SST; somatostatin [KO:K05237]
100436697  SSTR1; somatostatin receptor type 1 [KO:K04217]
100455484  SSTR2; somatostatin receptor type 2 [KO:K04218]
100462567  SSTR3; somatostatin receptor type 3 [KO:K04219]
100450419  SSTR5; somatostatin receptor type 5 [KO:K04221]
100456074  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100172679  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100458137  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 isoform X1 [KO:K04630]
100174748  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform 2 [KO:K04345] [EC:2.7.11.11]
100431906  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma isoform X1 [KO:K04345] [EC:2.7.11.11]
100437102  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100294619  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
100450554  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100462459  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100431578  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
100432292  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100436186  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100438869  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100127093  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100441756  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100439720  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100172895  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
100455260  EP300; histone acetyltransferase p300 isoform X2 [KO:K04498] [EC:2.3.1.48]
100445634  CREBBP; LOW QUALITY PROTEIN: CREB-binding protein [KO:K04498] [EC:2.3.1.48]
100435834  POU1F1; pituitary-specific positive transcription factor 1 isoform X2 [KO:K09363]
100462290  FOS; proto-oncogene c-Fos [KO:K04379]
100446663  chorionic somatomammotropin hormone 2 isoform X2 [KO:K05438]
100447767  growth hormone variant isoform X1 [KO:K05438]
100448861  GH1; somatotropin isoform X2 [KO:K05438]
103892869  chorionic somatomammotropin hormone 2-like isoform X1 [KO:K05438]
100452667  GHRL; appetite-regulating hormone isoform X1 [KO:K05254]
100441154  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
100452575  MRAP2; melanocortin-2 receptor accessory protein 2 isoform X1 [KO:K25968]
100458686  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
100460338  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100458716  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
100460060  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100434502  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
100461961  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100434355  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100439900  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
100451563  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100445922  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
100434318  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
100434127  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100433948  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100442085  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
100453904  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100431752  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
100451189  GHR; growth hormone receptor isoform X2 [KO:K05080]
100172517  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
100450941  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
100457650  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
100173225  SHC1; SHC-transforming protein 1 [KO:K06279]
100445042  SHC2; SHC-transforming protein 2 [KO:K17447]
100462011  SHC3; SHC-transforming protein 3 [KO:K17448]
100431574  SHC4; SHC-transforming protein 4 [KO:K17449]
100173972  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100434331  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100458733  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100459427  HRAS; GTPase HRas [KO:K02833]
100462513  KRAS; GTPase KRas isoform X1 [KO:K07827]
100174317  NRAS; GTPase NRas precursor [KO:K07828]
100173732  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
100446021  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100450988  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100169740  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100431824  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100173683  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100171541  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
100461695  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
100462537  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
100442255  IRS1; insulin receptor substrate 1 [KO:K16172]
100452233  IRS2; insulin receptor substrate 2 [KO:K07187]
100458662  IRS4; insulin receptor substrate 4 [KO:K17446]
100174298  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100173589  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100437617  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100432846  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100453779  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103889133  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100454279  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100448114  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100442100  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100456786  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100447772  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100444645  IGF1; insulin-like growth factor I isoform X2 [KO:K05459]
112130081  JUNB; transcription factor jun-B [KO:K09028]
100445635  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
100440378  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100446544  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100437823  IGFALS; LOW QUALITY PROTEIN: insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
100173070  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
100447959  PTK2; focal adhesion kinase 1 isoform X1 [KO:K05725] [EC:2.7.10.2]
103889518  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
100452410  CRK; adapter molecule crk isoform X1 [KO:K04438]
100443298  CRKL; crk-like protein [KO:K04438]
100453309  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
100457536  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform X1 [KO:K04432] [EC:2.7.12.2]
100439299  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
100448382  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform X1 [KO:K04433] [EC:2.7.12.2]
100174482  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
100459133  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100437424  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100449269  MAPK14; mitogen-activated protein kinase 14 isoform X2 [KO:K04441] [EC:2.7.11.24]
100449853  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
100437263  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100438358  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
pon04010  MAPK signaling pathway
pon04020  Calcium signaling pathway
pon04024  cAMP signaling pathway
pon04630  JAK-STAT signaling pathway
KO pathway
ko04935   
LinkDB

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