KEGG   PATHWAY: mdo04935
Entry
mdo04935                    Pathway                                
Name
Growth hormone synthesis, secretion and action - Monodelphis domestica (gray short-tailed opossum)
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
mdo04935  Growth hormone synthesis, secretion and action
mdo04935

Organism
Monodelphis domestica (gray short-tailed opossum) [GN:mdo]
Gene
100032812  GHRH; growth hormone releasing hormone [KO:K05260]
100029724  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
100021523  GNAS; GNAS complex locus [KO:K04632]
100029582  guanine nucleotide-binding protein G(s) subunit alpha [KO:K04632]
100030463  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
100013164  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
100025332  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
100030872  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
100019274  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
100013823  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
100026554  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
100013831  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
100018346  ADCY10; adenylate cyclase 10, soluble [KO:K11265] [EC:4.6.1.1]
100009770  SST; somatostatin [KO:K05237]
100029402  SSTR1; somatostatin receptor 1 [KO:K04217]
100028527  SSTR2; somatostatin receptor 2 [KO:K04218]
100025457  SSTR3; somatostatin receptor 3 [KO:K04219]
100616853  SSTR5; somatostatin receptor 5 [KO:K04221]
100013052  GNAI1; G protein subunit alpha i1 [KO:K04630]
100030095  GNAI3; G protein subunit alpha i3 [KO:K04630]
100032986  GNAI2; G protein subunit alpha i2 [KO:K04630]
100011211  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
100026861  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100032298  cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100014049  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
100025939  ATF2; activating transcription factor 2 [KO:K04450]
100012224  ATF4; activating transcription factor 4 [KO:K04374]
100017208  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
100020067  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
100022547  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
100015046  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
103104366  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
100032634  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
100025603  ATF6B; activating transcription factor 6 beta [KO:K09049]
100028102  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
100013876  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
100030334  POU1F1; POU class 1 homeobox 1 [KO:K09363]
100018285  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
554243  GH1; growth hormone 1 [KO:K05438]
100024400  GHRL; ghrelin and obestatin prepropeptide [KO:K05254]
100010258  GHSR; growth hormone secretagogue receptor [KO:K04284]
100018706  MRAP2; melanocortin 2 receptor accessory protein 2 [KO:K25968]
100011605  GNAQ; G protein subunit alpha q [KO:K04634]
100009763  GNA11; G protein subunit alpha 11 [KO:K04635]
100033281  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
100031660  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
100031869  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
100031263  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
100024674  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
100013346  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
100013305  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
100010212  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
100025596  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100013684  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
100021421  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
100014450  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
100019531  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
554180  GHR; growth hormone receptor [KO:K05080]
100017930  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
100032696  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
100027579  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
100016090  SHC1; SHC adaptor protein 1 [KO:K06279]
100024603  SHC3; SHC adaptor protein 3 [KO:K17448]
100031128  SHC4; SHC adaptor protein 4 [KO:K17449]
100022894  GRB2; growth factor receptor bound protein 2 [KO:K04364]
100618058  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
100029256  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
100032921  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
554186  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
554197  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
100022523  GTPase NRas-like [KO:K07828]
100015410  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
100018410  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100018044  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100028096  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100012916  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100028917  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
100011382  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
100012174  STAT5A; signal transducer and activator of transcription 5A [KO:K11223]
100011470  STAT5B; signal transducer and activator of transcription 5B [KO:K11224]
100021838  IRS1; insulin receptor substrate 1 [KO:K16172]
100025395  IRS4; insulin receptor substrate 4 [KO:K07187]
100023831  IRS2; insulin receptor substrate 2 [KO:K07187]
103100498  insulin receptor substrate 1-B-like [KO:K17445]
100019317  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
100032726  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
100616957  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
100010412  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
100017332  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
100024769  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
100014564  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
100019947  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
100027373  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
100619675  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
100012447  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
100021295  IGF1; insulin like growth factor 1 [KO:K05459]
100009986  JUNB; JunB proto-oncogene, AP-1 transcription factor subunit [KO:K09028]
100616780  suppressor of cytokine signaling 1-like [KO:K04694]
100011895  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
100026656  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100011409  IGFALS; insulin like growth factor binding protein acid labile subunit [KO:K17256]
100618843  IGFBP3; insulin like growth factor binding protein 3 [KO:K10138]
100027188  PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
100012317  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
100015312  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
100032065  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
100016872  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
100019828  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
100029049  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
100028089  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
100618895  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
100010279  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
100010891  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
100026324  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
100028821  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
mdo04010  MAPK signaling pathway
mdo04020  Calcium signaling pathway
mdo04024  cAMP signaling pathway
mdo04630  JAK-STAT signaling pathway
KO pathway
ko04935   
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