KEGG   PATHWAY: cge04935
Entry
cge04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Cricetulus griseus (Chinese hamster)
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
cge04935  Growth hormone synthesis, secretion and action
cge04935

Organism
Cricetulus griseus (Chinese hamster) [GN:cge]
Gene
100756401  Ghrh; somatoliberin isoform X1 [KO:K05260]
100772938  Ghrhr; growth hormone-releasing hormone receptor isoform X2 [KO:K04584]
100689067  Gnas; guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
103158534  neuroendocrine secretory protein 55 [KO:K04632]
100764561  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100773811  Adcy2; adenylate cyclase type 2 isoform X2 [KO:K08042] [EC:4.6.1.1]
100770498  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100768998  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
100765958  Adcy5; LOW QUALITY PROTEIN: adenylate cyclase type 5 isoform X2 [KO:K08045] [EC:4.6.1.1]
100768368  Adcy6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100756132  Adcy7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
113837458  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
100751372  Adcy9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100767272  Adcy10; adenylate cyclase type 10 [KO:K11265] [EC:4.6.1.1]
100774243  Sst; somatostatin [KO:K05237]
100766048  Sstr1; somatostatin receptor type 1 isoform X2 [KO:K04217]
100753171  Sstr2; somatostatin receptor type 2 [KO:K04218]
100750645  Sstr3; somatostatin receptor type 3 [KO:K04219]
100774959  Sstr5; somatostatin receptor type 5 [KO:K04221]
100689068  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100689072  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha [KO:K04630]
100689070  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100768997  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha isoform X2 [KO:K04345] [EC:2.7.11.11]
100767097  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
100761582  Creb1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100754663  Atf2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100689386  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100762192  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X2 [KO:K09048]
100771872  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X2 [KO:K09048]
100766300  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100774488  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100772940  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100764159  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
100767112  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100762260  Ep300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
100770451  histone lysine acetyltransferase CREBBP isoform X3 [KO:K04498] [EC:2.3.1.48]
100773365  Pou1f1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
100689418  Fos; proto-oncogene c-Fos [KO:K04379]
100770534  Gh1; somatotropin [KO:K05438]
100759101  Ghrl; appetite-regulating hormone isoform X2 [KO:K05254]
100755255  Ghsr; growth hormone secretagogue receptor type 1 [KO:K04284]
100760244  Mrap2; melanocortin-2 receptor accessory protein 2 [KO:K25968]
100689066  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
100689065  Gna11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100760134  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X2 [KO:K05858] [EC:3.1.4.11]
100760731  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100770957  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
100751979  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X2 [KO:K05858] [EC:3.1.4.11]
100766006  Prkca; protein kinase C alpha type isoform X2 [KO:K02677] [EC:2.7.11.13]
100760922  Prkcb; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
100762950  Prkcg; protein kinase C gamma type isoform X2 [KO:K19663] [EC:2.7.11.13]
100764450  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform X9 [KO:K04958]
100758965  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 isoform X2 [KO:K04959]
100751775  inositol 1,4,5-trisphosphate receptor type 3 isoform X3 [KO:K04960]
100765508  Cacna1s; voltage-dependent L-type calcium channel subunit alpha-1S isoform X5 [KO:K04857]
100754788  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C isoform X30 [KO:K04850]
100772497  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
100757994  Cacna1f; voltage-dependent L-type calcium channel subunit alpha-1F isoform X2 [KO:K04853]
100763540  Ghr; growth hormone receptor isoform X2 [KO:K05080]
100769337  Jak2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
100769697  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
100752475  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
100758936  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
100761269  Shc2; LOW QUALITY PROTEIN: SHC-transforming protein 2 [KO:K17447]
100760879  Shc3; SHC-transforming protein 3 isoform X2 [KO:K17448]
100763505  Shc4; SHC-transforming protein 4 isoform X2 [KO:K17449]
100769627  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
100757521  Sos1; son of sevenless homolog 1 isoform X2 [KO:K03099]
100769325  Sos2; son of sevenless homolog 2 isoform X3 [KO:K03099]
100773737  Hras; GTPase HRas isoform X2 [KO:K02833]
100763178  Kras; GTPase KRas isoform X4 [KO:K07827]
113839127  GTPase KRas-like [KO:K07827]
113837935  GTPase KRas-like isoform X2 [KO:K07827]
113837956  GTPase KRas-like [KO:K07827]
113838653  GTPase KRas-like isoform X2 [KO:K07827]
113838692  GTPase KRas-like [KO:K07827]
113838722  GTPase KRas-like isoform X1 [KO:K07827]
113838818  GTPase KRas-like [KO:K07827]
113837633  GTPase KRas-like isoform X1 [KO:K07827]
113838146  GTPase KRas-like isoform X1 [KO:K07827]
113838876  GTPase KRas-like [KO:K07827]
113838228  GTPase KRas-like isoform X1 [KO:K07827]
113839011  GTPase KRas-like [KO:K07827]
100771078  GTPase KRas-like isoform X2 [KO:K07827]
113837960  GTPase KRas-like [KO:K07827]
113838098  GTPase KRas-like [KO:K07827]
113838326  GTPase KRas-like [KO:K07827]
113838417  GTPase KRas-like isoform X1 [KO:K07827]
113838488  GTPase KRas-like [KO:K07827]
113838583  GTPase KRas-like isoform X1 [KO:K07827]
113838676  GTPase KRas-like [KO:K07827]
113838679  GTPase KRas-like isoform X1 [KO:K07827]
113838746  GTPase KRas-like [KO:K07827]
113838796  GTPase KRas-like isoform X1 [KO:K07827]
113838871  GTPase KRas-like [KO:K07827]
113838872  GTPase KRas-like [KO:K07827]
113838892  GTPase KRas-like [KO:K07827]
113838898  GTPase KRas-like [KO:K07827]
113838914  GTPase KRas-like [KO:K07827]
113838921  GTPase KRas-like [KO:K07827]
113838942  GTPase KRas-like isoform X1 [KO:K07827]
113838943  GTPase KRas-like isoform X1 [KO:K07827]
113839007  GTPase HRas-like isoform X1 [KO:K07827]
118239746  GTPase KRas-like isoform X1 [KO:K07827]
118239767  GTPase KRas-like isoform X1 [KO:K07827]
118239768  GTPase KRas-like [KO:K07827]
118239770  GTPase KRas-like [KO:K07827]
118239801  GTPase KRas-like [KO:K07827]
118239825  GTPase KRas-like isoform X1 [KO:K07827]
100757614  Nras; GTPase NRas [KO:K07828]
100769018  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
100689403  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
113835540  dual specificity mitogen-activated protein kinase kinase 1-like isoform X1 [KO:K04368] [EC:2.7.12.2]
103158537  dual specificity mitogen-activated protein kinase kinase 1-like isoform X2 [KO:K04368] [EC:2.7.12.2]
100774204  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X2 [KO:K04369] [EC:2.7.12.2]
100759514  Mapk1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:2.7.11.24]
100753149  Mapk3; mitogen-activated protein kinase 3 isoform X2 [KO:K04371] [EC:2.7.11.24]
100755609  Stat1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
100755865  Stat3; signal transducer and activator of transcription 3 isoform X9 [KO:K04692]
100755571  signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
100750571  signal transducer and activator of transcription 5B isoform X2 [KO:K11224]
100755710  Irs1; insulin receptor substrate 1 [KO:K16172]
100771848  Irs2; insulin receptor substrate 2 isoform X2 [KO:K07187]
100751390  insulin receptor substrate 1 [KO:K17445]
100773159  insulin receptor substrate 4 isoform X2 [KO:K17446]
100771181  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X2 [KO:K02649]
100750761  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100774067  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100689251  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100769225  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100689252  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
100768351  Akt2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100752454  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100769460  Akt1; RAC-alpha serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100755421  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100760865  Gsk3b; glycogen synthase kinase-3 beta isoform X7 [KO:K03083] [EC:2.7.11.26]
100751642  Igf1; insulin-like growth factor I isoform X1 [KO:K05459]
100756141  Junb; transcription factor jun-B isoform X2 [KO:K09028]
100751218  Socs1; suppressor of cytokine signaling 1 isoform X2 [KO:K04694]
100769267  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
100753202  Igfals; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
100764858  Igfbp3; insulin-like growth factor-binding protein 3 isoform X2 [KO:K10138]
100759464  Ptk2; focal adhesion kinase 1 isoform X5 [KO:K05725] [EC:2.7.10.2]
100768861  Bcar1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
100752014  Crkl; crk-like protein isoform X1 [KO:K04438]
100762827  Crk; adapter molecule crk isoform X2 [KO:K04438]
100770540  Map3k1; LOW QUALITY PROTEIN: mitogen-activated protein kinase kinase kinase 1 isoform X2 [KO:K04416] [EC:2.7.11.25]
100756793  Map2k3; dual specificity mitogen-activated protein kinase kinase 3 isoform X3 [KO:K04432] [EC:2.7.12.2]
100770977  Map2k4; dual specificity mitogen-activated protein kinase kinase 4 isoform X2 [KO:K04430] [EC:2.7.12.2]
100771767  dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
100771734  Mapk8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100754361  mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
100764964  Mapk9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100689104  Mapk14; mitogen-activated protein kinase 14 isoform X3 [KO:K04441] [EC:2.7.11.24]
100759172  Mapk11; mitogen-activated protein kinase 11 isoform X2 [KO:K04441] [EC:2.7.11.24]
100754042  Mapk12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100763519  Mapk13; mitogen-activated protein kinase 13 isoform X2 [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
cge04010  MAPK signaling pathway
cge04020  Calcium signaling pathway
cge04024  cAMP signaling pathway
cge04630  JAK-STAT signaling pathway
KO pathway
ko04935   
LinkDB

DBGET integrated database retrieval system