KEGG   PATHWAY: hsa04912
Entry
hsa04912                    Pathway                                
Name
GnRH signaling pathway - Homo sapiens (human)
Description
Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.
Class
Organismal Systems; Endocrine system
Pathway map
hsa04912  GnRH signaling pathway
hsa04912

Network
nt06323  KISS1-GnRH-LH/FSH-E2 signaling
  Element
N00873  GnRH-GnRHR-PLCB-PKC signaling pathway
Drug
D00573  Goserelin acetate (JP18/USP)
D00988  Gonadorelin hydrochloride (USP)
D00989  Leuprolide acetate (USP)
D00990  Nafarelin acetate (USAN)
D01685  Cetrorelix acetate (JAN/USAN)
D01831  Buserelin acetate (JAN/USAN)
D02116  Histrelin acetate
D02369  Histrelin (USAN/INN)
D02738  Abarelix (USAN/INN)
D03267  Gonadorelin diacetate (JP18)
D03701  Detirelix acetate (USAN)
D04302  Ganirelix acetate (JAN/USAN)
D04361  Gonadorelin acetate (USP)
D04405  Goserelin (USAN/INN)
D04644  Iturelix (USAN/INN)
D04823  Lutrelin acetate (USAN)
D05599  Prazarelix acetate (USAN)
D06247  Triptorelin (USAN/INN)
D06248  Triptorelin pamoate (USAN)
D07259  Buserelin (INN)
D07665  Cetrorelix (INN)
D07957  Fertirelin (INN)
D08010  Ganirelix (INN)
D08027  Gonadorelin (INN)
D08113  Leuprorelin (INN)
D08241  Nafarelin (INN)
D08635  Degarelix acetate (USAN)
D08649  Triptorelin acetate
D08901  Degarelix (INN/USAN)
D09335  Elagolix (USAN/INN)
D09336  Elagolix sodium (USAN)
D09400  Degarelix acetate (JAN)
D10618  Defactinib (USAN/INN)
D10888  Relugolix (JAN/USAN/INN)
D11351  Opigolix (USAN/INN)
D11608  Linzagolix (USAN/INN)
D11609  Linzagolix choline (JAN/USAN)
D12337  Leuprolide mesylate
Organism
Homo sapiens (human) [GN:hsa]
Gene
100137049  PLA2G4B; phospholipase A2 group IVB [KO:K16342] [EC:3.1.1.4]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
10746  MAP3K2; mitogen-activated protein kinase kinase kinase 2 [KO:K04420] [EC:2.7.11.25]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
1081  CGA; glycoprotein hormones, alpha polypeptide [KO:K08522]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
123745  PLA2G4E; phospholipase A2 group IVE [KO:K16342] [EC:3.1.1.4]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
163688  CALML6; calmodulin like 6 [KO:K02183]
1839  HBEGF; heparin binding EGF like growth factor [KO:K08523]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
1958  EGR1; early growth response 1 [KO:K09203]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
2002  ELK1; ETS transcription factor ELK1 [KO:K04375]
2185  PTK2B; protein tyrosine kinase 2 beta [KO:K05871] [EC:2.7.10.2]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
2488  FSHB; follicle stimulating hormone subunit beta [KO:K05250]
255189  PLA2G4F; phospholipase A2 group IVF [KO:K16342] [EC:3.1.1.4]
2767  GNA11; G protein subunit alpha 11 [KO:K04635]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
2778  GNAS; GNAS complex locus [KO:K04632]
2796  GNRH1; gonadotropin releasing hormone 1 [KO:K05252]
2797  GNRH2; gonadotropin releasing hormone 2 [KO:K05252]
2798  GNRHR; gonadotropin releasing hormone receptor [KO:K04280]
283748  PLA2G4D; phospholipase A2 group IVD [KO:K16342] [EC:3.1.1.4]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
3709  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
3972  LHB; luteinizing hormone subunit beta [KO:K08521]
4214  MAP3K1; mitogen-activated protein kinase kinase kinase 1 [KO:K04416] [EC:2.7.11.25]
4215  MAP3K3; mitogen-activated protein kinase kinase kinase 3 [KO:K04421] [EC:2.7.11.25]
4216  MAP3K4; mitogen-activated protein kinase kinase kinase 4 [KO:K04428] [EC:2.7.11.25]
4313  MMP2; matrix metallopeptidase 2 [KO:K01398] [EC:3.4.24.24]
4323  MMP14; matrix metallopeptidase 14 [KO:K07763] [EC:3.4.24.80]
468  ATF4; activating transcription factor 4 [KO:K04374]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
51806  CALML5; calmodulin like 5 [KO:K02183]
5321  PLA2G4A; phospholipase A2 group IVA [KO:K16342] [EC:3.1.1.4]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
5337  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
5338  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5580  PRKCD; protein kinase C delta [KO:K06068] [EC:2.7.11.13]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
5598  MAPK7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
5609  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
6416  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
6714  SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]
775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
778  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
779  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
801  CALM1; calmodulin 1 [KO:K02183]
805  CALM2; calmodulin 2 [KO:K02183]
808  CALM3; calmodulin 3 [KO:K02183]
810  CALML3; calmodulin like 3 [KO:K02183]
815  CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
816  CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
817  CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
818  CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
8605  PLA2G4C; phospholipase A2 group IVC [KO:K16342] [EC:3.1.1.4]
8681  JMJD7-PLA2G4B; JMJD7-PLA2G4B readthrough [KO:K16342] [EC:3.1.1.4]
91860  CALML4; calmodulin like 4 [KO:K02183]
998  CDC42; cell division cycle 42 [KO:K04393]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00219  Arachidonate
C00416  Phosphatidate
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
Reference
PMID:15350605
  Authors
Ruf F, Sealfon SC.
  Title
Genomics view of gonadotrope signaling circuits.
  Journal
Trends Endocrinol Metab 15:331-8 (2004)
DOI:10.1016/j.tem.2004.07.008
Reference
PMID:15613448
  Authors
Harrison GS, Wierman ME, Nett TM, Glode LM.
  Title
Gonadotropin-releasing hormone and its receptor in normal and malignant cells.
  Journal
Endocr Relat Cancer 11:725-48 (2004)
DOI:10.1677/erc.1.00777
Reference
PMID:15982836
  Authors
Pawson AJ, McNeilly AS.
  Title
The pituitary effects of GnRH.
  Journal
Anim Reprod Sci 88:75-94 (2005)
DOI:10.1016/j.anireprosci.2005.05.010
Reference
  Authors
DeGroot LJ, Jameson JL (ed).
  Title
Endocrinology (Fifth edition)
  Journal
Elsevier Saunders (2006)
Reference
PMID:10707049
  Authors
Naor Z, Benard O, Seger R.
  Title
Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor.
  Journal
Trends Endocrinol Metab 11:91-9 (2000)
DOI:10.1016/S1043-2760(99)00232-5
Reference
PMID:14596811
  Authors
Ruf F, Fink MY, Sealfon SC.
  Title
Structure of the GnRH receptor-stimulated signaling network: insights from genomics.
  Journal
Front Neuroendocrinol 24:181-99 (2003)
DOI:10.1016/S0091-3022(03)00027-X
Reference
PMID:12943720
  Authors
Farshori PQ, Shah BH, Arora KK, Martinez-Fuentes A, Catt KJ.
  Title
Activation and nuclear translocation of PKCdelta, Pyk2 and ERK1/2 by gonadotropin releasing hormone in HEK293 cells.
  Journal
J Steroid Biochem Mol Biol 85:337-47 (2003)
DOI:10.1016/S0960-0760(03)00226-7
Reference
PMID:15080147
  Authors
Shah BH, Catt KJ.
  Title
Matrix metalloproteinases in reproductive endocrinology.
  Journal
Trends Endocrinol Metab 15:47-9 (2004)
DOI:10.1016/j.tem.2004.01.004
Reference
PMID:12963732
  Authors
Roelle S, Grosse R, Aigner A, Krell HW, Czubayko F, Gudermann T.
  Title
Matrix metalloproteinases 2 and 9 mediate epidermal growth factor receptor transactivation by gonadotropin-releasing hormone.
  Journal
J Biol Chem 278:47307-18 (2003)
DOI:10.1074/jbc.M304377200
Reference
PMID:18708085
  Authors
Naor Z
  Title
Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor.
  Journal
Front Neuroendocrinol 30:10-29 (2009)
DOI:10.1016/j.yfrne.2008.07.001
Related
pathway
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04024  cAMP signaling pathway
hsa04060  Cytokine-cytokine receptor interaction
hsa04080  Neuroactive ligand-receptor interaction
KO pathway
ko04912   

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