KEGG   PATHWAY: mna04935
mna04935                    Pathway                                

Growth hormone synthesis, secretion and action - Miniopterus natalensis
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.
Organismal Systems; Endocrine system
Pathway map
mna04935  Growth hormone synthesis, secretion and action

Miniopterus natalensis [GN:mna]
107542103  GHRH; somatoliberin [KO:K05260]
107544385  GHRHR; growth hormone-releasing hormone receptor [KO:K04584]
107529329  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms short isoform X1 [KO:K04632]
107529353  neuroendocrine secretory protein 55-like [KO:K04632]
107526004  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:]
107540528  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:]
107534062  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:]
107531740  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:]
107527242  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:]
107528232  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:]
107531029  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:]
107539500  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:]
107535777  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:]
107529078  ADCY10; adenylate cyclase type 10 [KO:K11265] [EC:]
107527421  SST; somatostatin [KO:K05237]
107526113  SSTR1; somatostatin receptor type 1 [KO:K04217]
107528392  SSTR2; somatostatin receptor type 2 [KO:K04218]
107545271  SSTR3; somatostatin receptor type 3 [KO:K04219]
107533362  SSTR5; somatostatin receptor type 5 [KO:K04221]
107545320  GNAI3; guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
107540752  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
107545079  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
107544336  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:]
107543188  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:]
107524712  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
107532468  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
107531265  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
107525737  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
107543873  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
107530327  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
107544136  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
107544933  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
107544390  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
107539006  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
107535781  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:]
107531280  EP300; histone acetyltransferase p300 [KO:K04498] [EC:]
107524611  POU1F1; pituitary-specific positive transcription factor 1 isoform X1 [KO:K09363]
107533821  FOS; LOW QUALITY PROTEIN: proto-oncogene c-Fos [KO:K04379]
107531064  somatotropin-like [KO:K05438]
107534771  GHRL; appetite-regulating hormone [KO:K05254]
107533516  GHSR; growth hormone secretagogue receptor type 1 [KO:K04284]
107544926  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
107544328  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
107542967  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:]
107536366  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:]
107536369  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:]
107539797  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:]
107538300  PRKCA; protein kinase C alpha type [KO:K02677] [EC:]
107544745  PRKCB; protein kinase C beta type [KO:K19662] [EC:]
107540426  PRKCG; protein kinase C gamma type [KO:K19663] [EC:]
107529142  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
107525255  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
107541588  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
107536018  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
107546425  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
107534931  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
107541372  CACNA1F; LOW QUALITY PROTEIN: voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
107545625  GHR; growth hormone receptor [KO:K05080]
107538122  JAK2; tyrosine-protein kinase JAK2 [KO:K04447] [EC:]
107542131  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:]
107524904  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:]
107543890  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
107538554  SHC2; SHC-transforming protein 2 [KO:K17447]
107529164  SHC3; SHC-transforming protein 3 [KO:K17448]
107535558  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
107536618  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
107525851  SOS2; son of sevenless homolog 2 [KO:K03099]
107541780  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
107542351  HRAS; GTPase HRas isoform X1 [KO:K02833]
107525258  KRAS; GTPase KRas [KO:K07827]
107545303  NRAS; GTPase NRas [KO:K07828]
107534729  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
107533801  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
107525695  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
107541504  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:]
107530451  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
107540521  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
107528938  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
107528939  STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]
107528845  signal transducer and activator of transcription 5B-like [KO:K11224]
107525521  IRS1; LOW QUALITY PROTEIN: insulin receptor substrate 1 [KO:K16172]
107530378  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
107526265  IRS4; insulin receptor substrate 4 [KO:K17446]
107526728  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
107529317  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
107535325  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
107532628  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
107538463  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
107541106  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
107542383  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
107528331  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
107534199  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
107540994  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
107527219  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:]
107545147  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
107541524  JUNB; transcription factor jun-B [KO:K09028]
107525439  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
107538918  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
107532035  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
107533393  IGFALS; insulin-like growth factor-binding protein complex acid labile subunit [KO:K17256]
107526006  IGFBP3; insulin-like growth factor-binding protein 3 [KO:K10138]
107533206  PTK2; focal adhesion kinase 1 isoform X1 [KO:K05725] [EC:]
107524660  BCAR1; breast cancer anti-estrogen resistance protein 1 isoform X1 [KO:K05726]
107535608  CRK; adapter molecule crk isoform X1 [KO:K04438]
107530545  CRKL; crk-like protein [KO:K04438]
107527145  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:]
107542219  MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:]
107544551  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:]
107528394  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform X1 [KO:K04433] [EC:]
107537133  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:]
107527953  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:]
107528432  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:]
107545565  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
107545613  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:]
107536041  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
107536051  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
Nishad R, Mukhi D, Menon R K, Pasupulati A.
Growth Hormone and Metabolic Homeostasis
Eur Med J 6:78-87 (2018)
Lu M, Flanagan JU, Langley RJ, Hay MP, Perry JK
Targeting growth hormone function: strategies and therapeutic applications.
Signal Transduct Target Ther 4:3 (2019)
Argetsinger LS, Carter-Su C
Mechanism of signaling by growth hormone receptor.
Physiol Rev 76:1089-107 (1996)
Carter-Su C, Schwartz J, Smit LS
Molecular mechanism of growth hormone action.
Annu Rev Physiol 58:187-207 (1996)
Carter-Su C, Rui L, Herrington J
Role of the tyrosine kinase JAK2 in signal transduction by growth hormone.
Pediatr Nephrol 14:550-7 (2000)
Dehkhoda F, Lee CMM, Medina J, Brooks AJ
The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects.
Front Endocrinol (Lausanne) 9:35 (2018)
Carter-Su C, Schwartz J, Argetsinger LS
Growth hormone signaling pathways.
Growth Horm IGF Res 28:11-5 (2016)
Berryman DE, Henry B, Hjortebjerg R, List EO, Kopchick JJ
Developments in our understanding of the effects of growth hormone on white adipose tissue from mice: implications to the clinic.
Expert Rev Endocrinol Metab 11:197-207 (2016)
Zhu T, Goh EL, LeRoith D, Lobie PE
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).
J Biol Chem 273:33864-75 (1998)
Choi S (ed).
Encyclopedia of Signaling Molecules
Springer International Publishing
Gracia-Navarro F, Castano JP, Malagon MM, Sanchez-Hormigo A, Luque RM, Hickey GJ, Peinado JR, Delgado E, Martinez-Fuentes AJ
Research progress in the stimulatory inputs regulating growth hormone (GH) secretion.
Comp Biochem Physiol B Biochem Mol Biol 132:141-50 (2002)
Bertherat J
Nuclear effects of the cAMP pathway activation in somatotrophs.
Horm Res 47:245-50 (1997)
Tuggle CK, Trenkle A
Control of growth hormone synthesis.
Domest Anim Endocrinol 13:1-33 (1996)
Cohen LE, Hashimoto Y, Zanger K, Wondisford F, Radovick S
CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression.
J Clin Invest 104:1123-30 (1999)
Khatib N, Gaidhane S, Gaidhane AM, Khatib M, Simkhada P, Gode D, Zahiruddin QS
Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.
J Clin Diagn Res 8:MC13-7 (2014)
Lengyel AM
From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion.
Arq Bras Endocrinol Metabol 50:17-24 (2006)
Anderson LL, Jeftinija S, Scanes CG, Stromer MH, Lee JS, Jeftinija K, Glavaski-Joksimovic A
Physiology of ghrelin and related peptides.
Domest Anim Endocrinol 29:111-44 (2005)
Camina JP, Carreira MC, Micic D, Pombo M, Kelestimur F, Dieguez C, Casanueva FF
Regulation of ghrelin secretion and action.
Endocrine 22:5-12 (2003)
Yang SK, Steyn F, Chen C
Influence of membrane ion channel in pituitary somatotrophs by hypothalamic regulators.
Cell Calcium 51:231-9 (2012)
Melmed S
Acromegaly pathogenesis and treatment.
J Clin Invest 119:3189-202 (2009)
mna04010  MAPK signaling pathway
mna04020  Calcium signaling pathway
mna04024  cAMP signaling pathway
mna04630  JAK-STAT signaling pathway
KO pathway

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