KEGG   PATHWAY: pale04935
Entry
pale04935                   Pathway                                
Name
Growth hormone synthesis, secretion and action - Pteropus alecto (black flying fox)
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
pale04935  Growth hormone synthesis, secretion and action
pale04935

Organism
Pteropus alecto (black flying fox) [GN:pale]
Gene
102890766  GHRH; somatoliberin [KO:K05260]
102890068  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
102889764  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas [KO:K04632]
102884106  neuroendocrine secretory protein 55-like [KO:K04632]
102887497  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
102893265  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
102886232  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
102890575  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
102897495  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102890588  ADCY6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
102881535  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
102896789  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
102885676  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
102889468  ADCY10; adenylate cyclase type 10 [KO:K11265] [EC:4.6.1.1]
102887980  SST; somatostatin [KO:K05237]
102887676  SSTR1; somatostatin receptor type 1 [KO:K04217]
102887916  SSTR2; somatostatin receptor type 2 [KO:K04218]
102885753  SSTR3; somatostatin receptor type 3 [KO:K04219]
102891462  SSTR5; somatostatin receptor type 5 [KO:K04221]
102892785  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
102885642  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
102898665  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
102886679  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102877853  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102888198  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102889014  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
102896553  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
102878515  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
102894633  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
102882888  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
102886510  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
102879289  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
102884583  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
102898128  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X3 [KO:K09049]
102886172  CREBBP; LOW QUALITY PROTEIN: CREB-binding protein [KO:K04498] [EC:2.3.1.48]
102881042  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
102881097  POU1F1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
102891428  FOS; proto-oncogene c-Fos [KO:K04379]
102888823  somatotropin [KO:K05438]
102891071  GHRL; appetite-regulating hormone [KO:K05254]
102885425  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
102893479  MRAP2; melanocortin-2 receptor accessory protein 2 [KO:K25968]
102877919  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
102888619  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
102879238  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
102885207  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
102885781  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
102885953  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
102887078  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
102880663  PRKCB; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
102888961  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
102894982  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
102896356  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
102881783  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
102896136  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
102882682  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X2 [KO:K04850]
102888351  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
102893611  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
102891638  GHR; growth hormone receptor [KO:K05080]
102882079  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
102896228  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
102883128  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
102894443  SHC1; LOW QUALITY PROTEIN: SHC-transforming protein 1 [KO:K06279]
102885958  SHC2; SHC-transforming protein 2 [KO:K17447]
102879956  SHC3; SHC-transforming protein 3 [KO:K17448]
102888926  SHC4; SHC-transforming protein 4 [KO:K17449]
102878822  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
102882462  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
102889597  SOS2; son of sevenless homolog 2 [KO:K03099]
102896270  HRAS; GTPase HRas isoform X3 [KO:K02833]
102895590  KRAS; GTPase KRas isoform X1 [KO:K07827]
102885950  NRAS; GTPase NRas isoform X2 [KO:K07828]
102893439  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
102897122  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
102879034  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102895390  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102885749  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102886603  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
102884374  STAT3; LOW QUALITY PROTEIN: signal transducer and activator of transcription 3 [KO:K04692]
102884638  signal transducer and activator of transcription 5A [KO:K11223]
102884882  signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
102891583  IRS1; insulin receptor substrate 1 [KO:K16172]
102898575  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
102895007  IRS4; insulin receptor substrate 4 [KO:K17446]
102879163  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
102891637  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X3 [KO:K02649]
102879453  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102889227  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102880320  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102889576  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102885144  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102879337  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102898305  AKT2; LOW QUALITY PROTEIN: RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102885092  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102882441  GSK3B; glycogen synthase kinase-3 beta isoform X4 [KO:K03083] [EC:2.7.11.26]
102890331  IGF1; insulin-like growth factor I isoform X3 [KO:K05459]
102879600  JUNB; transcription factor jun-B [KO:K09028]
102878735  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
102889529  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
102887834  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
102885090  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
102891216  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
102898998  PTK2; focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
102897097  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X2 [KO:K05726]
102898080  CRKL; crk-like protein [KO:K04438]
102885553  CRK; adapter molecule crk isoform X1 [KO:K04438]
102886741  MAP3K1; LOW QUALITY PROTEIN: mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
102886389  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform X1 [KO:K04432] [EC:2.7.12.2]
102894945  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X3 [KO:K04430] [EC:2.7.12.2]
102888822  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
102885064  MAPK10; mitogen-activated protein kinase 10 isoform X5 [KO:K04440] [EC:2.7.11.24]
102890689  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102892777  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
102895900  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
102888602  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
102888845  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
102877720  MAPK13; mitogen-activated protein kinase 13 [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
pale04010  MAPK signaling pathway
pale04020  Calcium signaling pathway
pale04024  cAMP signaling pathway
pale04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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