KEGG   PATHWAY: sara04935
Entry
sara04935                   Pathway                                
Name
Growth hormone synthesis, secretion and action - Sorex araneus (European shrew)
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
sara04935  Growth hormone synthesis, secretion and action
sara04935

Organism
Sorex araneus (European shrew) [GN:sara]
Gene
101550605  GHRH; somatoliberin [KO:K05260]
101538715  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
101539470  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
101557843  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101539413  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101547055  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101539776  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
101551819  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101549131  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
101543858  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101550559  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101551730  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101537843  ADCY10; adenylate cyclase type 10 [KO:K11265] [EC:4.6.1.1]
101539656  SST; somatostatin [KO:K05237]
101537215  SSTR1; somatostatin receptor type 1 [KO:K04217]
101540248  SSTR2; somatostatin receptor type 2 [KO:K04218]
101540915  SSTR3; somatostatin receptor type 3 [KO:K04219]
101547659  SSTR5; somatostatin receptor type 5 [KO:K04221]
101544375  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
101538556  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101545200  guanine nucleotide-binding protein G(i) subunit alpha-like [KO:K04630]
101545636  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101539926  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101555578  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101546696  cAMP-dependent protein kinase catalytic subunit-like [KO:K04345] [EC:2.7.11.11]
101554719  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
101552417  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101539734  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101539159  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101554214  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101538215  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
101543170  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101542980  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101553377  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
101554016  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
101551180  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
101542504  EP300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
101558222  CREBBP; CREB-binding protein [KO:K04498] [EC:2.3.1.48]
101545574  POU1F1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
101545059  FOS; proto-oncogene c-Fos isoform X1 [KO:K04379]
101547182  somatotropin [KO:K05438]
101537318  GHRL; appetite-regulating hormone [KO:K05254]
101537161  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
101541069  MRAP2; melanocortin-2 receptor accessory protein 2 [KO:K25968]
101557809  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101544809  GNA11; guanine nucleotide-binding protein subunit alpha-11 isoform X1 [KO:K04635]
101551223  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
101546811  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
101547690  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101559179  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
101551961  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101547658  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
101539279  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101556467  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
101556630  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
101555935  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
101543389  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
101557862  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X3 [KO:K04850]
101546311  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
101548753  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
101540370  GHR; growth hormone receptor [KO:K05080]
101550196  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:2.7.10.2]
101545860  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
101554088  PLCG2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
101553821  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
101550526  SHC2; SHC-transforming protein 2 [KO:K17447]
101550468  SHC3; SHC-transforming protein 3 [KO:K17448]
101537303  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
101544020  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
101550972  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
101555769  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101546777  HRAS; GTPase HRas [KO:K02833]
101557531  KRAS; GTPase KRas isoform X1 [KO:K07827]
101559343  NRAS; GTPase NRas [KO:K07828]
101545329  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101550720  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101555057  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101559341  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101541587  mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
101545848  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101554357  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
101552896  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
101552631  signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
101552185  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
101542323  IRS1; insulin receptor substrate 1 [KO:K16172]
101552515  IRS2; insulin receptor substrate 2 [KO:K07187]
101548071  insulin receptor substrate 1-like [KO:K17445]
101540547  IRS4; insulin receptor substrate 4 isoform X1 [KO:K17446]
101547106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101541868  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101540938  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101542917  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101556597  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101548304  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
101543096  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101559009  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
101543371  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101554656  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101536841  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
101554190  IGF1; insulin-like growth factor I isoform X4 [KO:K05459]
101550183  JUNB; transcription factor jun-B [KO:K09028]
101551995  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
101545288  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
101555243  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
101542659  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
101554973  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
101540332  PTK2; focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
101557104  BCAR1; breast cancer anti-estrogen resistance protein 1 [KO:K05726]
101543637  CRK; adapter molecule crk isoform X1 [KO:K04438]
101547306  CRKL; crk-like protein [KO:K04438]
101554394  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
101555912  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform X1 [KO:K04432] [EC:2.7.12.2]
101542924  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
101542881  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
101538553  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
101556557  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
101556063  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
101536977  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
101537598  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
101554044  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
101545321  MAPK12; mitogen-activated protein kinase 12 [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
sara04010  MAPK signaling pathway
sara04020  Calcium signaling pathway
sara04024  cAMP signaling pathway
sara04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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