KEGG   PATHWAY: npo04935
Entry
npo04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Nyctereutes procyonoides (raccoon dog)
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
npo04935  Growth hormone synthesis, secretion and action
npo04935

Organism
Nyctereutes procyonoides (raccoon dog) [GN:npo]
Gene
129498491  GHRH; somatoliberin [KO:K05260]
129502922  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
129497792  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
129497848  neuroendocrine secretory protein 55 [KO:K04632]
129512833  guanine nucleotide-binding protein G(s) subunit alpha-like isoform X1 [KO:K04632]
129515724  LOW QUALITY PROTEIN: adenylate cyclase type 1-like [KO:K08041] [EC:4.6.1.1]
129516202  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
129498939  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
129510932  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
129499511  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
129503910  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
129517234  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
129513386  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
129502672  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
129519450  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
129508573  ADCY10; adenylate cyclase type 10 [KO:K11265] [EC:4.6.1.1]
129512837  adenylate cyclase type 10-like [KO:K11265] [EC:4.6.1.1]
129498851  SST; somatostatin [KO:K05237]
129499343  SSTR1; somatostatin receptor type 1 isoform X1 [KO:K04217]
129515278  SSTR2; somatostatin receptor type 2 isoform X1 [KO:K04218]
129511957  SSTR3; somatostatin receptor type 3 [KO:K04219]
129520086  SSTR5; somatostatin receptor type 5 [KO:K04221]
129494269  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
129519569  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
129522106  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
129519960  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
129521768  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
129522997  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
129518269  cyclic AMP-responsive element-binding protein 1-like [KO:K05870]
129498595  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
129511576  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
129508719  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
129494799  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
129503105  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
129515926  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
129522278  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
129502771  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
129513003  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
129511409  EP300; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
129520280  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
129502355  POU1F1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
129496401  FOS; protein c-Fos [KO:K04379]
129511661  somatotropin [KO:K05438]
129522261  GHRL; appetite-regulating hormone isoform X1 [KO:K05254]
129498395  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
129512708  MRAP2; melanocortin-2 receptor accessory protein 2 isoform X1 [KO:K25968]
129500644  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
129522061  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
129496894  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
129504276  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
129497646  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
129500550  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
129494612  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
129519978  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
129500385  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
129521608  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
129505465  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
129512495  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
129505985  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
129503382  CACNA1C; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
129521343  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
129517804  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
129509486  GHR; growth hormone receptor isoform X1 [KO:K05080]
129499911  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
129493567  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
129497753  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
129508769  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
129522289  SHC2; SHC-transforming protein 2 [KO:K17447]
129500459  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
129506392  SHC4; SHC-transforming protein 4 [KO:K17449]
129511906  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
129496132  SOS2; son of sevenless homolog 2 [KO:K03099]
129510881  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
129494224  HRAS; GTPase HRas isoform X1 [KO:K02833]
129505561  KRAS; GTPase KRas isoform X1 [KO:K07827]
129501466  NRAS; GTPase NRas [KO:K07828]
129522592  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
129506345  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
129522322  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
129502349  mitogen-activated protein kinase 3-like [KO:K04371] [EC:2.7.11.24]
129507918  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
129519082  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
129522804  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
129506479  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
129513286  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
129508314  signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
129523419  IRS1; insulin receptor substrate 1 [KO:K16172]
129516510  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
129518021  IRS4; insulin receptor substrate 4 [KO:K17446]
129513452  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
129520803  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
129522073  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
129496789  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
129498637  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
129507069  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
129508823  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129495892  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129499851  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
129517633  RAC-alpha serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
129514778  RAC-alpha serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
129513263  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
129503652  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
129516962  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
129521835  JUNB; transcription factor JunB [KO:K09028]
129519759  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
129516951  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
129497119  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
129519451  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
129516210  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
129502645  PTK2; focal adhesion kinase 1 isoform X1 [KO:K05725] [EC:2.7.10.2]
129497226  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
129508118  CRKL; crk-like protein [KO:K04438]
129513703  CRK; adapter molecule crk isoform X1 [KO:K04438]
129513743  MAP3K1; mitogen-activated protein kinase kinase kinase 1 isoform X1 [KO:K04416] [EC:2.7.11.25]
129497110  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
129497178  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
129508745  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform X1 [KO:K04433] [EC:2.7.12.2]
129494670  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
129501796  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
129522825  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
129511619  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
129511620  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
129512956  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
129512957  MAPK14; mitogen-activated protein kinase 14 isoform X1 [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
npo04010  MAPK signaling pathway
npo04020  Calcium signaling pathway
npo04024  cAMP signaling pathway
npo04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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