KEGG   PATHWAY: lav04935
Entry
lav04935                    Pathway                                

Name
Growth hormone synthesis, secretion and action - Loxodonta africana (African savanna elephant)
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
lav04935  Growth hormone synthesis, secretion and action
lav04935

Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100674910  GHRH; somatoliberin [KO:K05260]
100670783  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
100655206  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100669226  neuroendocrine secretory protein 55-like [KO:K04632]
100671072  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100673570  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100674724  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100675525  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
100670244  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100653532  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100653771  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100661616  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100663448  ADCY9; LOW QUALITY PROTEIN: adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100655094  ADCY10; adenylate cyclase type 10 isoform X1 [KO:K11265] [EC:4.6.1.1]
100656123  SST; somatostatin [KO:K05237]
100665784  SSTR1; LOW QUALITY PROTEIN: somatostatin receptor type 1 [KO:K04217]
100660893  SSTR2; somatostatin receptor type 2 [KO:K04218]
100670370  SSTR3; somatostatin receptor type 3 [KO:K04219]
100671401  SSTR5; somatostatin receptor type 5 [KO:K04221]
100666344  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100670234  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100667957  GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100656966  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100674245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100675162  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100657989  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100662521  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374]
100653565  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100673694  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100666211  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100670574  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100677344  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100675079  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100666885  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100661096  EP300; LOW QUALITY PROTEIN: histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
100663731  LOW QUALITY PROTEIN: CREB-binding protein [KO:K04498] [EC:2.3.1.48]
100660860  POU1F1; pituitary-specific positive transcription factor 1 [KO:K09363]
100674799  FOS; LOW QUALITY PROTEIN: proto-oncogene c-Fos [KO:K04379]
100662962  somatotropin [KO:K05438]
100658388  GHRL; appetite-regulating hormone [KO:K05254]
100660018  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
100656672  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100675896  guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100670617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
100672435  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100668575  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100663829  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100665537  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100672078  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
100671733  PRKCG; LOW QUALITY PROTEIN: protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100665028  ITPR1; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
100667845  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
100659666  ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100673089  CACNA1S; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
100659992  CACNA1D; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
100674649  CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
100660760  GHR; growth hormone receptor [KO:K05080]
100676652  JAK2; tyrosine-protein kinase JAK2 isoform X1 [KO:K04447] [EC:2.7.10.2]
100677739  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100658990  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
100653766  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
100659669  SHC3; SHC-transforming protein 3 [KO:K17448]
100654827  SHC4; SHC-transforming protein 4 [KO:K17449]
100655474  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100657379  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
100656200  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100661512  KRAS; GTPase KRas isoform X2 [KO:K07827]
100659051  NRAS; GTPase NRas [KO:K07828]
100655727  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100667623  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100657587  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100658240  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100665157  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100668424  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100669583  STAT3; signal transducer and activator of transcription 3 isoform X2 [KO:K04692]
100672448  signal transducer and activator of transcription 5A [KO:K11223]
100669299  STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]
100664968  IRS1; insulin receptor substrate 1 [KO:K16172]
100676904  IRS2; insulin receptor substrate 2 isoform X3 [KO:K07187]
100660353  LOW QUALITY PROTEIN: insulin receptor substrate 1-like [KO:K17445]
100667324  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
100653731  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100665045  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100675496  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100657948  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100658340  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100666266  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100663184  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100657536  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100660187  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100660112  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100675105  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100664710  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
100654706  JUNB; transcription factor jun-B [KO:K09028]
100664110  SOCS1; LOW QUALITY PROTEIN: suppressor of cytokine signaling 1 [KO:K04694]
100660067  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100670741  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100666000  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
100674990  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
100668436  PTK2; LOW QUALITY PROTEIN: focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
100675124  BCAR1; LOW QUALITY PROTEIN: breast cancer anti-estrogen resistance protein 1 [KO:K05726]
100659273  CRK; adapter molecule crk isoform X1 [KO:K04438]
100662046  CRKL; crk-like protein [KO:K04438]
100655149  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
100675607  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform X1 [KO:K04432] [EC:2.7.12.2]
100655007  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
100662511  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
100654943  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100674229  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100673395  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100673331  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
100656926  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100661039  MAPK12; mitogen-activated protein kinase 12 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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  Authors
Melmed S
  Title
Acromegaly pathogenesis and treatment.
  Journal
J Clin Invest 119:3189-202 (2009)
DOI:10.1172/JCI39375
Related
pathway
lav04010  MAPK signaling pathway
lav04020  Calcium signaling pathway
lav04024  cAMP signaling pathway
lav04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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