Human Thyroid Stimulating Hormone (TSH) signaling pathway (Homo sapiens)

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CCND3CCND3MAP2K1PMAPK3PPIK3R2IP3PKAcAMPPIP2DAGPIP3ProteinCYEnzyme ComplexTSH Signal Transduction PathwayReceptorLigandmRNACell proliferationNUHRASBRAFFOSCGATTF1GNB1TTF2STAT1 SCRIBRAF1TSHBJUNPAX8GNG2E2F1KCNIP3EGR1MYCPTSHRSTAT3PPDPK1PPIK3CAPIK3R1CDK2PPSRCpMAP2K3MAP2K6PPAKT1PPRKCZRPS6KB1MAPK1PPRB1PCREB1PDE4DPPGNAI1GNA13GTPGNAI2GTPGNA12GTPGNAO1GTPGNAQGTPGTPGNAI3GTPMYL12BRALGDSDePGNASJAK2GTPPJAK1PRPS6MTORPADCY2ADCY3CDK2PCDK4PRPS6KA1PPLD1PLCB1RAP1BRAP1AGTPGTPRHOACCNE1MAPK14PCDKN1BCCND3CDK4PRAP1GAPPNUCYPKANUCYSmall moleculeInduced activationInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationProteinDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageProteinMoleculeAPEX1APEX1NUCY


Description

Human thyroid stimulating hormone (TSH) is a glycoprotein secreted by the anterior part of the pituitary gland (1). TSH plays an important physiological role in the regulation of the hypothalamic-pituitary-thyroid axis by modulating the release of the thyroid hormones from the thyroid gland. TSH is mainly expressed in adenohypophysis , thyroid gland, leukocyte, pituitary gland, stratum basale, stratum corneum, stratum granulosum, stratum spinosum and keratinocyte (2-4). Impairment of TSH signal transduction pathway leads to thyroid disorders such as goitre, hypothyroidism and hyperthyroidism, with complex clinical manifestations.

TSH is a heterodimer with one alpha and one beta subunit associated non-covalently. The binding of TSHB to TSHR triggers conformational changes that are transmitted through the intracellular receptor domains to promote coupling between the receptor and its cognate heterotrimeric G proteins. The TSHR activation stimulates the catalytic exchange of GDP for GTP on the Ga subunit and subsequently induces the dissociation of the GTP-bound Ga subunit from the Gß? subunit heterodimer. TSHR is reported to interact with GNA12, GNA13, GNAQ, GNAO1, GNAI2, GNAI1, GNAI3, GNAS and GNA11 G-protein subunits (5). Once dissociated, free Ga-GTP and Gß? subunits regulate the activity of enzymatic effectors, such as adenylate cyclases to generate cAMP (6, 7). cAMP activate Rap1A (Ras-Related Protein-1A) and Rap1B (Ras-Related Protein Rap1B) (8, 9). cAMP productions leads to the activation of PKA by the dissociation of regulatory subunits. Activated PKA phosphorylates its target proteins. One of the PKA substrate is the nuclear transcription factor CREB, which activates the transcription of cAMP-responsive genes after upon phosphorylation by PKA (10, 11).

TSHR also mediates its effects through Janus Kinases and Ras effectors. JAK kinases phosphorylate and activate STAT transcription factor, particularly STAT1 and STAT3 (12, 13, 14)¬¬¬¬. RAS is a guanine nucleotide-binding protein that is a key intermediate in signal transduction pathways. The RAS activation, followed by BRAF recruitment leads to the activation of the MAP kinases (ERK1/2). ERKs, once activated, translocates to the nucleus to phosphorylate several nuclear targets. In addition to JAK/STAT and Ras/MAP kinase pathways, TSH also activates PI3K (Phosphoinositide-3 Kinase). A major downstream target of PI3K pathway is the serine/threonine Kinase AKT that is involved in mediating stimulation of cell proliferation by inhibiting apoptosis (15, 16). AKT and MTOR raptor complex phosphorylation leads to activation of downstream signaling.

Comments

GenMAPP notes 
NetPath_23 - TSH signaling pathway. NetPath (http://www.netpath.org) is a collaborative project between PandeyLab at Johns Hopkins University (http://pandeylab.igm.jhmi.edu) and the Institute of Bioinformatics (http://www.ibioinformatics.org). If you use this pathway, you must cite the NetPath website until the pathway is published.
GenMAPP remarks 
http://www.netpath.org

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Ontology Terms

 

Bibliography

  1. Telikicherla D, Ambekar A, Palapetta SM, Dwivedi SB, Raju R, Sharma J, Prasad TsK, Ramachandra Y, Mohan SS, Maharudraiah J, Mukherjee S, Pandey A; ''A comprehensive curated resource for follicle stimulating hormone signaling.''; BMC Res Notes, 2011 PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
104862view15:14, 20 June 2019DeSlUpdated arrows to translocation
104861view15:10, 20 June 2019DeSlAdded lit. ref.
104859view15:04, 20 June 2019DeSlLauren has fixed legens (interactions to graphical line), connected lines in the figure, and updated interactions to MIM-types if available.
104856view14:56, 20 June 2019L DupuisConverted graphical representation of transcription and translation from lines to mim conversion type
104847view14:37, 20 June 2019L DupuisConverted interactions to graphical lines in legend. Connected unconnected lines
104844view14:35, 20 June 2019L DupuisConverted interactions to graphical lines in legend. Connected unconnected lines
104840view14:23, 20 June 2019L DupuisConverted interactions to graphical lines in legend. Connected unconnected lines
104838view14:18, 20 June 2019L DupuisConverted interactions to graphical lines in legend. Connected unconnected lines
89823view11:59, 6 October 2016MkutmonReverted to version '11:58, 6 October 2016' by Mkutmon
89822view11:58, 6 October 2016MkutmonModified description
89821view11:58, 6 October 2016MkutmonModified description
89820view11:58, 6 October 2016MkutmonModified description
86081view10:11, 29 June 2016MirellaKalafatiModified title
79960view13:13, 28 April 2015Zarichanged data node to label for protein box
78548view10:30, 7 January 2015MaintBotadded missing graphIds
75384view21:24, 21 May 2014KhanspersRemoved GenMAPP notes/comments
72116view23:06, 24 October 2013AlexanderPicoadded missing database to xref
71988view11:11, 24 October 2013MkutmonChanged Unknown -> GeneProduct for PIK3R2
71538view19:23, 17 October 2013MaintBotremoved data source from nodes without identifier
71336view17:23, 17 October 2013MaintBotRemoved empty labels with height = 0.0
70105view18:55, 12 July 2013MaintBotupdated to 2013 schema
67727view11:55, 26 June 2013DdiglesOntology Term : 'thyroid-stimulating hormone signaling pathway' added !
44635view18:24, 22 September 2011KhanspersModified categories
44634view18:23, 22 September 2011KhanspersModified description
44561view14:04, 20 September 2011DrrenugoelNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADCY2GeneProduct108 (Entrez Gene)
ADCY3GeneProduct109 (Entrez Gene)
AKT1GeneProduct207 (Entrez Gene)
APEX1GeneProduct328 (Entrez Gene)
BRAFGeneProduct673 (Entrez Gene)
CCND3GeneProduct896 (Entrez Gene)
CCNE1GeneProduct898 (Entrez Gene)
CDK2GeneProduct1017 (Entrez Gene)
CDK4GeneProduct1019 (Entrez Gene)
CDKN1BGeneProduct1027 (Entrez Gene)
CGAGeneProduct1081 (Entrez Gene)
CREB1GeneProduct1385 (Entrez Gene)
E2F1Rna1869 (Entrez Gene)
EGR1Rna1958
FOSRna2353 (Entrez Gene)
GNA12GeneProduct2768 (Entrez Gene)
GNA13GeneProduct10672 (Entrez Gene)
GNAI1GeneProduct2770 (Entrez Gene)
GNAI2GeneProduct2771 (Entrez Gene)
GNAI3GeneProduct2773 (Entrez Gene)
GNAO1GeneProduct2775 (Entrez Gene)
GNAQGeneProduct2776 (Entrez Gene)
GNASGeneProduct2778 (Entrez Gene)
GNB1GeneProduct2782 (Entrez Gene)
GNG2GeneProduct54331 (Entrez Gene)
HRASGeneProduct3265 (Entrez Gene)
JAK1GeneProduct3716 (Entrez Gene)
JAK2GeneProduct3717 (Entrez Gene)
JUNRna3725 (Entrez Gene)
KCNIP3GeneProduct30818 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP2K3GeneProduct5606 (Entrez Gene)
MAP2K6GeneProduct5608 (Entrez Gene)
MAPK14GeneProduct1432 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
MTORGeneProduct2475 (Entrez Gene)
MYCRna4609 (Entrez Gene)
MYL12BGeneProduct103910 (Entrez Gene)
PAX8Rna7849 (Entrez Gene)
PDE4DGeneProduct5144 (Entrez Gene)
PDPK1GeneProduct5170 (Entrez Gene)
PIK3CAGeneProduct5290 (Entrez Gene)
PIK3R1GeneProduct5295 (Entrez Gene)
PIK3R25296 (Entrez Gene)
PLCB1GeneProduct23236 (Entrez Gene)
PLD1GeneProduct5337 (Entrez Gene)
PRKCZGeneProduct5934 (Entrez Gene)
ProteinProtein5894 (Entrez Gene)
ProteinGeneProduct
RAF1GeneProduct5894 (Entrez Gene)
RALGDSGeneProduct5900 (Entrez Gene)
RAP1AGeneProduct5906 (Entrez Gene)
RAP1BGeneProduct5908 (Entrez Gene)
RAP1GAPGeneProduct5909 (Entrez Gene)
RB1GeneProduct5925 (Entrez Gene)
RHOAGeneProduct3480 (Entrez Gene)
RPS6GeneProduct6194 (Entrez Gene)
RPS6KA1GeneProduct6195 (Entrez Gene)
RPS6KB1GeneProduct6198 (Entrez Gene)
SCRIBGeneProduct23513 (Entrez Gene)
SRCGeneProduct6714 (Entrez Gene)
STAT1 GeneProduct6772 (Entrez Gene)
STAT3GeneProduct6774 (Entrez Gene)
TSHBGeneProduct7252 (Entrez Gene)
TSHRGeneProduct7253 (Entrez Gene)
TTF1Rna7270 (Entrez Gene)
TTF2Rna8458 (Entrez Gene)

Annotated Interactions

No annotated interactions
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