KEGG   PATHWAY: lve04935
Entry
lve04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Lipotes vexillifer (Yangtze River dolphin)
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
lve04935  Growth hormone synthesis, secretion and action
lve04935

Organism
Lipotes vexillifer (Yangtze River dolphin) [GN:lve]
Gene
103072618  GHRH; somatoliberin isoform X1 [KO:K05260]
103087131  GHRHR; growth hormone-releasing hormone receptor isoform X1 [KO:K04584]
103089051  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas-like [KO:K04632]
103085385  neuroendocrine secretory protein 55-like [KO:K04632]
103081539  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
103084817  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
103076182  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
103075499  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
103091169  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
103075153  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
103078677  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
103085845  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
103070451  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
103068449  adenylate cyclase type 10-like [KO:K11265] [EC:4.6.1.1]
103087922  ADCY10; adenylate cyclase type 10 [KO:K11265] [EC:4.6.1.1]
103087046  SST; somatostatin [KO:K05237]
103085366  SSTR1; somatostatin receptor type 1 [KO:K04217]
103091199  SSTR2; somatostatin receptor type 2 [KO:K04218]
103076809  SSTR3; somatostatin receptor type 3 [KO:K04219]
103076265  SSTR5; somatostatin receptor type 5 [KO:K04221]
103080185  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
103077308  GNAI2; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
103081367  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 isoform X1 [KO:K04630]
103077464  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
103074112  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
103075978  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
103089070  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
103083306  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
103086171  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
103085711  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
103087008  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
103091030  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
103071696  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
103081811  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
103069101  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
103079020  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
103070724  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
103079084  POU1F1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
103084433  FOS; proto-oncogene c-Fos isoform X1 [KO:K04379]
103072956  uncharacterized protein LOC103072956 [KO:K04379]
103077460  GH1; somatotropin [KO:K05438]
103081566  GHRL; appetite-regulating hormone isoform X1 [KO:K05254]
103089904  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
103076950  MRAP2; melanocortin-2 receptor accessory protein 2 [KO:K25968]
103082420  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
103076924  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
103086280  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
103083884  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
103078639  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
103079287  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
103073028  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
103090549  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
103086653  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
103079294  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
103078697  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
103070387  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
103090575  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
103087340  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
103074544  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
103082192  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
103069416  GHR; growth hormone receptor isoform X1 [KO:K05080]
103076804  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
103068930  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
103070997  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
103074885  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
103088833  SHC2; SHC-transforming protein 2 [KO:K17447]
103078122  SHC3; SHC-transforming protein 3 [KO:K17448]
103088900  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
103079766  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
103079242  SOS1; son of sevenless homolog 1 [KO:K03099]
103081084  SOS2; son of sevenless homolog 2-like [KO:K03099]
103076043  HRAS; GTPase HRas isoform X1 [KO:K02833]
103077579  KRAS; GTPase KRas [KO:K07827]
103068734  NRAS; GTPase NRas [KO:K07828]
103087933  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
103082805  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
103090769  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
103070260  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
103075543  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
103069117  LOW QUALITY PROTEIN: signal transducer and activator of transcription 1-like [KO:K11220]
103086495  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
103082535  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
103082258  STAT5B; LOW QUALITY PROTEIN: signal transducer and activator of transcription 5B [KO:K11224]
103074278  IRS1; insulin receptor substrate 1 [KO:K16172]
103088704  IRS2; insulin receptor substrate 2 [KO:K07187]
103068740  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
103070370  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
103078725  PIK3R3; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
103083960  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
103089257  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
103088756  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
103085303  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103084975  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103076365  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103068921  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
103083889  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
103074757  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
103078928  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
103085209  JUNB; transcription factor jun-B [KO:K09028]
103089381  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
103070250  SOCS2; suppressor of cytokine signaling 2 isoform X1 [KO:K04695]
103071774  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
103069456  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
103082081  IGFBP3; insulin-like growth factor-binding protein 3 isoform X1 [KO:K10138]
103082438  PTK2; focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
103077564  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
103087905  CRK; adapter molecule crk isoform X1 [KO:K04438]
103090463  CRKL; crk-like protein [KO:K04438]
103083385  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
103091611  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
103091203  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
103081641  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 6-like [KO:K04433] [EC:2.7.12.2]
103084630  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
103087676  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
103078792  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
103083209  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
103077530  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
103078049  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
103078710  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
lve04010  MAPK signaling pathway
lve04020  Calcium signaling pathway
lve04024  cAMP signaling pathway
lve04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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