Corticotropin-releasing hormone signaling pathway (Homo sapiens)

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PRKCQPNOcGMPRegulation of CRHCYProinflammatory effect in leukocytesCYNUGuanylateENActivated inkeratinocytesthymocytesPlacentalvesselvasodilationNUCorticotropin-Releasing Hormone Signaling PathwaymRNAInhibited inmelanocytespituitary corticotrophspituitary tumor cellsCyclaseFatty acidoxidationNUAdenylateNUCYENDesensitizationIncreased gap junctionsNeuroprotectionVEGF releasein mast cellsFASL releasein PC12 cellsCYPMRecycling of receptorsApoptosis inMicroglial cellsHippocampal neuronsProstate cancer cellsNUCYDehydroepiandrosterone sulfate and cortisol productionKeratinocytedifferentiationand proliferationCell survivalNUCYNUPMCYNeuronalsurvivalInhibits Cell proliferationACACANR4A1FOSL1SP1CRHCACNA1HJUNPTK2IL18NCOA2RHOAIL8NR4A1CRHBPNOS3FOSPRKAPRKAA2JUNBJUNDTRIM28FOSBFOSL2TLR4S80PT172PRKCIPPRKCDPHSD3B1TCF4TFAP2ACTNNB1ACTH productionMAPK3T204T202IL2KRT1MAPK9T183Y185NR4A2CRHR2MAPK1CRHY187Y185SP1CYP11A1HSP90AA1IVLCRHR1NR4A1S386S412S301TFAP2ACRHCRHR1EPACCTNNB1KRT14Enzyme complexTranslocation DeubiquitinationActivationInhibitionAcetylationNegative regulation of gene expressionLEGENDLeads to through unknown mechanismPhosphorylationProtein-protein interactionTransportUbiquitinationDephosphorylationInduced catalysisAuto catalysisSumoylationPositive regulation of gene expressionReceptorLigandProteinDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageRELAPRKCBPPRKCAPGNAQCREB1S133PRKAcAMPGNB5GNB3GNB2GNB1ADRBK2GNA11GNAO1GNASGNAI2GNAI1DAGIP3PIP2MAP2K1BRAFRAP1BPLCG2PLCB3PS537PLCG1PGSK3BS9PARP1PCCASP9PCCASP3PCCASP12PCMAPK8T183Y185MAP3K5PERNPCYP21A2CYP17A1STARCYP11B1CYP11A1CAMK2AHSD3B2GRK6ADRBK2ECE1NFKBIAPCGJA1CRHR2ARRB1SULT2A1ADRBK2CRHARRB2RELABCL2PI3KAKT1S473POMCNR4A2FOSCalciumPMCYARRB1ARRB2PMCYECE1CRHCRHR1CRHR2CRHCRHR1T399CRHCyclaseGNAZELK1TBX19FOSG-gammaInhibits Progesterone synthesis in Placental trophoblastspathwayDegradationand dissociationof NFKBsNFKB1NFKB1NFKB1MAPK14Y182T180NR4A1AP-1 complexClathrin and arrestin mediated endocytosisENPMPro-inflammatorycytokine productionCRHCRHBPProtein


Corticotropin-releasing hormone (CRH) is a neuropeptide secreted abundantly in the paraventricular nucleus of the hypothalamus, amygdala, cerebral cortex and cerebellum in the central nervous system. It is also expressed in adrenal gland, placenta, testis, spleen, gut, thymus and skin. CRH is the principal mediator of endocrine stress response. CRH also plays a significant role in inflammatory responses, hemodynamic actions, stromal cell decidualization during estrus cycle, implantation of blastocyst, maintenance of pregnancy, onset of labor and neuroprotection. Excess secretion of CRH during severe depression and its association with increased levels of cortisol have been observed. CRH has also been reported to be involved in anxiety disorders, anorexia nervosa. Decrease in cortical CRH content has been observed in Alzheimer's disease and Parkinson's disease.

The actions of CRH are mediated through class II/secretin-like family type of G-protein coupled receptor (GPCR) called the CRH receptors (CRHR). CRH is a high affinity ligand of CRHR1 and also binds to CRHR2 but with lower affinity. CRH receptors do not have any intrinsic kinase activity and transduce the signal via the heterotrimeric G-proteins. The CRH receptors are rapidly desensitized by G-protein-coupled receptor kinase (GRK) and β-arrestin mechanisms in the presence of high concentrations of CRH. Binding of CRH to CRH receptor induces a conformational change in the receptor by activating it. This further activates Gα-subunit and its subsequent dissociation from the Gβγ dimer. CRH receptors on interaction with Gα-subunit of different G-proteins such as Gαs, Gαi/o, Gαq/11 activate numerous downstream signaling cascades and result in the induction of various cellular responses. The pathways that are activated upon CRH stimulation are: Adenylate cyclase/cAMP/PKA, PLC/PKC, ERK/MAPK, PI3K-AKT and NF-kappa B.

CRH binding to CRHR1 couples G-stimulatory (Gs) protein which in turn activates cAMP-dependent protein kinase (PKA). Activation of PKA leads to the phosphorylation of transcription factors like cAMP response element binding protein (CREB), which in turn increases the expression of pro-opiomelanocortin (POMC) gene and the release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal glands and thereby mediates changes associated with stress response. CREB also regulates genes containing the Ca2+/cAMP response element such as FOS. The activation of cAMP by CRH induces the mRNA expression and transcription of orphan nuclear receptors NR4A1 and NR4A2, which in turn transcriptionally activates the expression of POMC. Activation of cAMP/PKA can also induce the expression of enzymes involved in dehydroepiandrosterone sulfate and cortisol production. The biological functions of CRH are also mediated by MAPK family, in particular MAPK1/3 and MAPK14. MAPK1/3 mediates activation of transcription factors NR4A1 and NR4A2 and induction of POMC in corticotrophs. MAPK14 is involved in CRH-induced inhibition of IL-18 expression in human keratinocytes. The CRHR1/PKA/ERK signaling activate the transcription factors - ELK1, SP1 and TFAP2A. SP1 and TFAP2A up-regulates the expression of ADRBK2, which causes the desensitization of CRHR1 receptors.

The PLC/PKC pathway is activated by coupling of the CRH receptors to the Gαq/11 proteins. This cascade stimulates the formation of IP3 and contributes to the mobilization of intracellular calcium. Calcium is involved in the transcription regulation of FOS as well as NR4A1 and NR4A2 through CAMK2A. PLC/PKC is involved in the activation of AP-1 complex and subsequent transcriptional regulation of genes involved in keratinocyte differentiation and proliferation – KRT1, KRT14 and IVL. This cascade also inhibits the expression of CYP11A1 and HSD3B1, the genes involved in progesterone synthesis in placental trophoblasts. Another important signaling pathway activated upon CRH stimulation is the nitric oxide (NO)/cGMP, involved in the control of vascular tone. In human keratinocytes, upon CRH stimulation, NFKBIA degradation is diminished and the activity of NFKB is inhibited resulting in the down-regulation of NFKB-dependent genes IL2 and HSP90AA1 and inhibition of cell proliferation. The gene involved in cell survival, BCL2 is transcriptionally regulated via the PI3K/AKT. Please access this pathway at NetSlim database.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal


NetPath - Corticotropin-releasing hormone. NetPath ( is a collaborative project between PandeyLab at Johns Hopkins University ( and the Institute of Bioinformatics ( If you use this pathway, you must cite the NetPath website until the pathway is published.

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108254view14:14, 3 December 2019L DupuisConverted interactions to graphical lines in legend
108206view11:02, 29 November 2019FehrhartOntology Term : 'Alzheimer's disease' added !
108205view11:02, 29 November 2019FehrhartOntology Term : 'Parkinson's disease' added !
108204view11:01, 29 November 2019FehrhartOntology Term : 'major depressive disorder' added !
108203view11:01, 29 November 2019FehrhartOntology Term : 'anorexia nervosa' added !
106369view00:54, 23 August 2019KhanspersModified description
105563view06:19, 9 August 2019KhanspersModified description
97622view07:46, 31 May 2018AMTanModified description
94191view14:21, 25 August 2017Mkutmonadded missing metabolite identifier
94190view14:16, 25 August 2017Mkutmonadded missing metabolite identifiers
90017view19:26, 8 October 2016AlexanderPicoModified description
89805view11:41, 6 October 2016Mkutmonfixed special characters in description
88987view11:26, 18 August 2016MirellaKalafatiModified title
79973view07:00, 29 April 2015Zariannotated IL8,CYP11A1 and changed box for protein and mRNA
79562view15:34, 25 March 2015Zariadded ID for EPAC gene
78490view10:28, 7 January 2015MaintBotadded missing graphIds
71393view18:58, 17 October 2013MaintBotRemoved source from datanodes with empty id
67947view09:32, 28 June 2013DdiglesOntology Term : 'corticotropin-releasing hormone signaling pathway' added !
63171view20:28, 8 May 2013MaintBotUpdating gpml version
61292view21:59, 6 April 2013MaintBot
61291view21:58, 6 April 2013MaintBot
61290view21:56, 6 April 2013MaintBotremoved old publication references
61233view17:33, 5 April 2013MaintBotupdated pathway elements from provided gpml
57669view20:15, 31 January 2013KhanspersModified categories
57322view15:26, 25 January 2013NetPathSpecify description
53380view04:50, 6 November 2012NetPathModified description
53379view04:46, 6 November 2012NetPathModified description
53378view04:41, 6 November 2012NetPathNew pathway

External references


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NameTypeDatabase referenceComment
ACACAGeneProduct31 (Entrez Gene)
ACTH production
ADRBK2GeneProduct157 (Entrez Gene)
AKT1GeneProduct207 (Entrez Gene)
ARRB1GeneProduct408 (Entrez Gene)
ARRB2GeneProduct409 (Entrez Gene)
BCL2GeneProduct596 (Entrez Gene)
BRAFGeneProduct673 (Entrez Gene)
CACNA1HGeneProduct8912 (Entrez Gene)
CAMK2AGeneProduct815 (Entrez Gene)
CASP12GeneProduct100506742 (Entrez Gene)
CASP3GeneProduct836 (Entrez Gene)
CASP9GeneProduct842 (Entrez Gene)
CREB1GeneProduct1385 (Entrez Gene)
CRHGeneProduct1392 (Entrez Gene)
CRHBPGeneProduct1393 (Entrez Gene)
CRHR1GeneProduct1394 (Entrez Gene)
CRHR2GeneProduct1395 (Entrez Gene)
CTNNB1GeneProduct1499 (Entrez Gene)
CYP11A1GeneProduct1583 (Entrez Gene)
CYP11B1GeneProduct1584 (Entrez Gene)
CYP17A1GeneProduct1584 (Entrez Gene)
CYP21A2GeneProduct1589 (Entrez Gene)
CalciumMetaboliteQ23905776 (Wikidata)
DAGMetaboliteQ161466 (Wikidata)
ECE1GeneProduct1889 (Entrez Gene)
ELK1GeneProduct2002 (Entrez Gene)
EPACGeneProduct10411 (Entrez Gene)
ERNGeneProduct2081 (Entrez Gene)
FOSGeneProduct2353 (Entrez Gene)
FOSBGeneProduct2354 (Entrez Gene)
FOSL1GeneProduct8061 (Entrez Gene)
FOSL2GeneProduct2355 (Entrez Gene)
GJA1GeneProduct2697 (Entrez Gene)
GNA11GeneProduct2767 (Entrez Gene)
GNAI1GeneProduct2770 (Entrez Gene)
GNAI2GeneProduct2771 (Entrez Gene)
GNAO1GeneProduct2775 (Entrez Gene)
GNAQGeneProduct2776 (Entrez Gene)
GNASGeneProduct2778 (Entrez Gene)
GNAZGeneProduct2781 (Entrez Gene)
GNB1GeneProduct2782 (Entrez Gene)
GNB2GeneProduct2783 (Entrez Gene)
GNB3GeneProduct2784 (Entrez Gene)
GNB5GeneProduct10681 (Entrez Gene)
GRK6GeneProduct2870 (Entrez Gene)
GSK3BGeneProduct2932 (Entrez Gene)
HSD3B1GeneProduct3283 (Entrez Gene)
HSD3B2GeneProduct3284 (Entrez Gene)
HSP90AA1GeneProduct3320 (Entrez Gene)
IL18GeneProduct3606 (Entrez Gene)
IL2GeneProduct3558 (Entrez Gene)
IL8GeneProduct3576 (Entrez Gene)
IP3MetaboliteQ26998374 (Wikidata)
IVLGeneProduct3713 (Entrez Gene)
JUNGeneProduct3726 (Entrez Gene)
JUNBGeneProduct3727 (Entrez Gene)
JUNDGeneProduct3728 (Entrez Gene)
KRT1GeneProduct3848 (Entrez Gene)
KRT14GeneProduct3861 (Entrez Gene)
LigandGeneProduct7040 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP3K5GeneProduct4217 (Entrez Gene)
MAPK14GeneProduct1432 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
MAPK8GeneProduct5599 (Entrez Gene)
MAPK9GeneProduct5601 (Entrez Gene)
NCOA2GeneProduct10499 (Entrez Gene)
NFKB1GeneProduct4790 (Entrez Gene)
NFKBIAGeneProduct4792 (Entrez Gene)
NOS3GeneProduct4846 (Entrez Gene)
NR4A1GeneProduct3164 (Entrez Gene)
NR4A2GeneProduct4929 (Entrez Gene)
PARP1GeneProduct142 (Entrez Gene)
PIP2MetaboliteQ3083814 (Wikidata)
PLCB3GeneProduct1394 (Entrez Gene)
PLCG1GeneProduct5335 (Entrez Gene)
PLCG2GeneProduct5336 (Entrez Gene)
POMCGeneProduct5443 (Entrez Gene)
PRKAA2GeneProduct5563 (Entrez Gene)
PRKCAGeneProduct5578 (Entrez Gene)
PRKCBGeneProduct5579 (Entrez Gene)
PRKCDGeneProduct5580 (Entrez Gene)
PRKCIGeneProduct5584 (Entrez Gene)
PRKCQGeneProduct5588 (Entrez Gene)
PTK2GeneProduct5747 (Entrez Gene)
ProteinProtein5894 (Entrez Gene)
RAP1BGeneProduct5908 (Entrez Gene)
RELAGeneProduct5970 (Entrez Gene)
RHOAGeneProduct387 (Entrez Gene)
ReceptorGeneProduct7040 (Entrez Gene)
SP1GeneProduct6667 (Entrez Gene)
STARGeneProduct6770 (Entrez Gene)
SULT2A1GeneProduct6822 (Entrez Gene)
TBX19GeneProduct9095 (Entrez Gene)
TCF4GeneProduct6925 (Entrez Gene)
TFAP2AGeneProduct7020 (Entrez Gene)
TLR4GeneProduct7099 (Entrez Gene)
TRIM28GeneProduct10155 (Entrez Gene)
cAMPMetaboliteQ210041 (Wikidata)

Annotated Interactions

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