KEGG   PATHWAY: ncar04935
Entry
ncar04935                   Pathway                                
Name
Growth hormone synthesis, secretion and action - Sciurus carolinensis (gray squirrel)
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
ncar04935  Growth hormone synthesis, secretion and action
ncar04935

Organism
Sciurus carolinensis (gray squirrel) [GN:ncar]
Gene
124978144  somatoliberin-like isoform X1 [KO:K05260]
124991191  growth hormone-releasing hormone receptor [KO:K04584]
124978161  neuroendocrine secretory protein 55 [KO:K04632]
124975134  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
124990345  adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
124987010  adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
124962927  adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
124978229  LOW QUALITY PROTEIN: adenylate cyclase type 4-like [KO:K08044] [EC:4.6.1.1]
124992559  adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
124983776  adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
124966834  adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
124965096  adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
124970113  LOW QUALITY PROTEIN: adenylate cyclase type 9-like [KO:K08049] [EC:4.6.1.1]
124989568  adenylate cyclase type 10-like isoform X1 [KO:K11265] [EC:4.6.1.1]
124961065  adenylate cyclase type 10 [KO:K11265] [EC:4.6.1.1]
124993501  somatostatin [KO:K05237]
124972219  somatostatin receptor type 1 [KO:K04217]
124979671  somatostatin receptor type 2 [KO:K04218]
124982589  LOW QUALITY PROTEIN: somatostatin receptor type 3-like [KO:K04219]
124970709  somatostatin receptor type 5 [KO:K04221]
124992673  guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
124988012  guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
124991078  guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
124985819  cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
124969119  cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
124979032  cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
124979831  LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2-like [KO:K04450]
124984025  cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
124991113  cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
124958938  cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
124984689  cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
124969564  cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
124964377  cyclic AMP-responsive element-binding protein 3-like isoform X1 [KO:K09048]
124991182  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
124988573  cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
124969981  CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
124982357  histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
124993481  pituitary-specific positive transcription factor 1 [KO:K09363]
124977967  protein c-Fos [KO:K04379]
124978972  somatotropin [KO:K05438]
124970958  appetite-regulating hormone isoform X1 [KO:K05254]
124993493  growth hormone secretagogue receptor type 1 [KO:K04284]
124988948  melanocortin-2 receptor accessory protein 2 isoform X1 [KO:K25968]
124964255  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
124968563  guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
124976705  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
124959812  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
124977474  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
124972679  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
124979014  protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
124970211  LOW QUALITY PROTEIN: protein kinase C beta type-like [KO:K19662] [EC:2.7.11.13]
124967611  protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
124970932  inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
124983533  inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
124988553  inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
124961645  voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
124982084  voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
124968359  LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D-like [KO:K04851]
124971751  voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
124987665  growth hormone receptor [KO:K05080]
124964444  LOW QUALITY PROTEIN: tyrosine-protein kinase JAK2-like [KO:K04447] [EC:2.7.10.2]
124977089  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
124966613  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
124982298  SHC-transforming protein 1 isoform X1 [KO:K06279]
124975378  SHC-transforming protein 2-like [KO:K17447]
124965516  SHC-transforming protein 3 isoform X1 [KO:K17448]
124978227  SHC-transforming protein 4 [KO:K17449]
124980188  growth factor receptor-bound protein 2 [KO:K04364]
124977045  son of sevenless homolog 2 [KO:K03099]
124963384  son of sevenless homolog 1 isoform X1 [KO:K03099]
124974041  LOW QUALITY PROTEIN: son of sevenless homolog 2-like [KO:K03099]
124958599  GTPase HRas isoform X1 [KO:K02833]
124991017  GTPase KRas-like [KO:K07827]
124982118  GTPase KRas isoform X1 [KO:K07827]
124962389  GTPase NRas [KO:K07828]
124971006  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
124977990  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
124969568  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
124990635  LOW QUALITY PROTEIN: mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
124970294  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
124979200  signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
124978933  signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
124980612  signal transducer and activator of transcription 5A [KO:K11223]
124979870  signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
124979751  insulin receptor substrate 1 [KO:K16172]
124984569  insulin receptor substrate 2 [KO:K07187]
124970787  insulin receptor substrate 1-like [KO:K17445]
124972126  insulin receptor substrate 4 [KO:K17446]
124986648  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
124968815  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
124993166  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
124993330  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
124963509  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
124962260  LOW QUALITY PROTEIN: RAC-gamma serine/threonine-protein kinase-like [KO:K04456] [EC:2.7.11.1]
124976076  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
124966582  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
124979992  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
124992642  LOW QUALITY PROTEIN: glycogen synthase kinase-3 beta-like [KO:K03083] [EC:2.7.11.26]
124983128  insulin-like growth factor I isoform X1 [KO:K05459]
124969179  transcription factor JunB [KO:K09028]
124970442  suppressor of cytokine signaling 1 [KO:K04694]
124983925  suppressor of cytokine signaling 2 [KO:K04695]
124981264  suppressor of cytokine signaling 3 [KO:K04696]
124970517  insulin-like growth factor-binding protein complex acid labile subunit isoform X1 [KO:K17256]
124991742  insulin-like growth factor-binding protein 3 [KO:K10138]
124964882  focal adhesion kinase 1 isoform X1 [KO:K05725] [EC:2.7.10.2]
124967218  breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
124991190  crk-like protein [KO:K04438]
124980118  adapter molecule crk isoform X1 [KO:K04438]
124986862  LOW QUALITY PROTEIN: mitogen-activated protein kinase kinase kinase 1-like [KO:K04416] [EC:2.7.11.25]
124980599  dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
124980435  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 4-like [KO:K04430] [EC:2.7.12.2]
124981341  dual specificity mitogen-activated protein kinase kinase 6 isoform X1 [KO:K04433] [EC:2.7.12.2]
124986765  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
124994121  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
124984745  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
124988515  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
124989076  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
124978202  mitogen-activated protein kinase 14-like isoform X1 [KO:K04441] [EC:2.7.11.24]
124982485  mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
124982486  LOW QUALITY PROTEIN: mitogen-activated protein kinase 11-like [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
ncar04010  MAPK signaling pathway
ncar04020  Calcium signaling pathway
ncar04024  cAMP signaling pathway
ncar04630  JAK-STAT signaling pathway
KO pathway
ko04935   
LinkDB

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