KEGG   PATHWAY: ko04912
Entry
ko04912                     Pathway                                
Name
GnRH signaling pathway
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
ko04912  GnRH signaling pathway
ko04912

Drug
D03694  Deslorelin (USAN/INN)
D04174  Fertirelin acetate (USAN)
Orthology
K01115  PLD1_2; phospholipase D1/2 [EC:3.1.4.4]
K01398  MMP2; matrix metalloproteinase-2 (gelatinase A) [EC:3.4.24.24]
K02183  CALM; calmodulin
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K02833  HRAS; GTPase HRas
K03099  SOS; son of sevenless
K04280  GNRHR; gonadotropin-releasing hormone receptor
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04361  EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]
K04364  GRB2; growth factor receptor-bound protein 2
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04374  ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04375  ELK1; ETS domain-containing protein Elk-1
K04393  CDC42; cell division control protein 42
K04416  MAP3K1, MEKK1; mitogen-activated protein kinase kinase kinase 1 [EC:2.7.11.25]
K04420  MAP3K2, MEKK2; mitogen-activated protein kinase kinase kinase 2 [EC:2.7.11.25]
K04421  MAP3K3, MEKK3; mitogen-activated protein kinase kinase kinase 3 [EC:2.7.11.25]
K04428  MAP3K4, MEKK4; mitogen-activated protein kinase kinase kinase 4 [EC:2.7.11.25]
K04430  MAP2K4, MKK4; mitogen-activated protein kinase kinase 4 [EC:2.7.12.2]
K04431  MAP2K7, MKK7; mitogen-activated protein kinase kinase 7 [EC:2.7.12.2]
K04432  MAP2K3, MKK3; mitogen-activated protein kinase kinase 3 [EC:2.7.12.2]
K04433  MAP2K6, MKK6; mitogen-activated protein kinase kinase 6 [EC:2.7.12.2]
K04440  JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04441  P38; p38 MAP kinase [EC:2.7.11.24]
K04448  JUN; transcription factor AP-1
K04464  MAPK7; mitogen-activated protein kinase 7 [EC:2.7.11.24]
K04515  CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04635  GNA11; guanine nucleotide-binding protein subunit alpha-11
K04850  CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851  CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853  CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857  CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04958  ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959  ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K05250  FSHB; follitropin subunit beta
K05252  GNRH; gonadotropin-releasing hormone
K05704  SRC; tyrosine-protein kinase Src [EC:2.7.10.2]
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K05871  PTK2B, FAK2; focal adhesion kinase 2 [EC:2.7.10.2]
K06068  PRKCD; novel protein kinase C delta type [EC:2.7.11.13]
K07763  MMP14; matrix metalloproteinase-14 (membrane-inserted) [EC:3.4.24.80]
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K08521  LHB; lutropin subunit beta
K08522  CGA; glycoprotein hormones alpha chain
K08523  HBEGF; heparin-binding EGF-like growth factor
K09203  EGR1; early growth response protein 1
K16342  PLA2G4, CPLA2; cytosolic phospholipase A2 [EC:3.1.1.4]
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
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
ko04010  MAPK signaling pathway
ko04020  Calcium signaling pathway
ko04024  cAMP signaling pathway
ko04060  Cytokine-cytokine receptor interaction
ko04080  Neuroactive ligand-receptor interaction

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