Growth hormone receptor signaling (Homo sapiens)

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1, 7, 10, 17413, 186, 20821162112149, 1519, 22193endosome lumencytosolnucleoplasmIRS1,2p-Y701-STAT1 SOCS3 GrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimer:p-STAT5Growth Hormone SOCS1 ATPp-5Y-GHR(19-638) p-Y694-STAT5A GH1 p-Y1007-JAK2 GHR(19-638) GH2 p-STAT5 dimerGH2 p-T202,Y204-MAPK3 GH2 STAT5B GHR(19-638) STAT3 Activatedcytokine-likehormone receptors,p-Y1007-JAK2JAK2 GH1 SOCS2 GH1 STAT5B ADAM17JAK2 SOCS2 PTPN6 GrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimer:SHP2PRLR STAT5A GH2 GH2 ADPGH1 p-5Y-GHR(19-638) SOCS1 PTPN1 p-Y705-STAT3 CSH1 p-Y1007-JAK2 p-5Y-GHR(19-638) GH2 p-5Y-GHR(19-638) GH1 p-Y1007-JAK2 GHBP:GHRSOCS1 PRLR CISH Zn2+ GH2 p-STAT5A, p-STAT5BLYN GrowthHormone:ActivatedGrowthHormoneReceptor:p(Y1007)-JAK2 dimer:STAT1/STAT3STAT3 Growth HormoneReceptor-JAK2 dimerPTPN6 GH2 SOCS2 p-T,Y MAPKsGH2 Activatedcytokine-likehormone receptorsGH1 GH1 ATPGrowth Hormone:Growth HormoneReceptor-JAK2 dimerGH2 p-T185,Y187-MAPK1 CISH GH2 PTPN1 PRL p-Y694-STAT5A GrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimer:SOCSPTPN1Growth Hormone:Activated GrowthHormone Receptor-p(Y1007)-JAK2 dimerp-Y1007-JAK2 GH1 p-5Y-GHR(19-638) GH1 p-Y1007-JAK2 GHR(19-256) ATPGrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimerGHR activated GH2 PRL JAK2 p-Y1007-JAK2 p-Y-IRS2 JAK2 Growth Hormone:TyrosinephosphorylatedGrowth HormoneReceptor-JAK2dimer:SHP1GH2 Growth Hormone Growth Hormone GH1 IRS2 STAT1, STAT3p-Y694-STAT5A p-Y694-STAT5A MAPK3 p-5Y-GHR(19-638) ADPGHR(19-256) LYNPTPN6Zn2+ STAT5A GH2 ADPGHR activated GH2 p-Y1007-JAK2 Growth Hormone:Activated GrowthHormoneReceptor-JAK2 dimerp-Y-IRS1 GH1 ADPPRLRligands:ActivatedPRLR:JAK2dimer:SH2B1 betaSH2B1-2 Growth HormoneSOCS1 SOCSGHR activated GrowthHormone:p(Y332,487,627)-Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SHP2GH1 p-Y699-STAT5B GH1 H2OGrowth hormoneoligomerGH2 p-Y332,Y487,Y627-GHR(19-638) GH2 p-5Y-GHR(19-638) STAT1 GH1 p-Y1007-JAK2 p-Y1007-JAK2 GHR activated MAPK1 GHR(19-256)PRLR SOCS3 p-Y699-STAT5B ATPGrowthHormone:GrowthHormoneReceptor-JAK2dimer:LYNGHBP:GHJAK2 PTPN1 GH2 JAK2 MAPKsGrowthHormone:ActivatedGrowthHormoneReceptor:p(Y1007)-JAK2 dimer:p(Y701)-STAT1/p(Y705)-STAT3CSH1 SOCS2 GHR(19-638) PRL Zn2+ CSH1 GH2 p-Y699-STAT5B ADPPiGH1 STAT1 IRS1 STAT5A,STAT5BJAK2 GHR(257-638)ADPSOCS3 p-Y699-STAT5B GH1 GrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimer:SHP1p-Y1007-JAK2 GH1 Growth HormoneReceptor:JAK2CISH GH1 p-Y-IRS1,p-Y-IRS2Pip-Y1007-JAK2 CISH GHR(19-638) p-Y1007-JAK2 GH1 ATPGHR(19-638)GrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimer:STAT5ATPH2OPiGH2 GHR activated GHR(19-638) GHR(19-638)JAK2 p-5Y-GHR(19-638) SOCS3 GrowthHormone:TyrosinephosphorylatedGrowthHormoneReceptor-p(Y1007)-JAK2 dimer:CIS/SOCS1-3JAK2 p-STAT5 dimerCIS, SOCS1-3Growth Hormone:TyrosinephosphorylatedGrowth HormoneReceptor-JAK2dimer:SHP2p-5Y-GHR(19-638) GHR activated GH1 JAK25, 12


Description

Growth hormone (Somatotropin or GH) is a key factor in determining lean body mass, stimulating the growth and metabolism of muscle, bone and cartilage cells, while reducing body fat. It has many other roles; it acts to regulate cell growth, differentiation, apoptosis, and reorganisation of the cytoskeleton, affecting diverse processes such as cardiac function, immune function, brain function, and aging. GH also has insulin-like effects such as stimulating amino acid transport, protein synthesis, glucose transport, and lipogenesis. The growth hormone receptor (GHR) is a a member of the cytokine receptor family. When the dimeric receptor binds GH it undergoes a conformational change which leads to phosphorylation of key tyrosine residues in its cytoplasmic domains and activation of associated tyrosine kinase JAK2. This leads to recruitment of signaling molecules such as STAT5 and Src family kinases such as Lyn leading to ERK activation. The signal is attenuated by association of Suppressor of Cytokine Signaling (SOCS) proteins and SHP phosphatases which bind to or dephosphorylate specific phosphorylated tyrosines on GHR/JAK. The availability of GHR on the cell surface is regulated by at least two processes; internalization and cleavage from the suface by metalloproteases. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 982772
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jupe, Steve

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Deng L, He K, Wang X, Yang N, Thangavel C, Jiang J, Fuchs SY, Frank SJ.; ''Determinants of growth hormone receptor down-regulation.''; PubMed Europe PMC
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  3. Behrmann I, Janzen C, Gerhartz C, Schmitz-Van de Leur H, Hermanns H, Heesel B, Graeve L, Horn F, Tavernier J, Heinrich PC.; ''A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation.''; PubMed Europe PMC
  4. Rowlinson SW, Yoshizato H, Barclay JL, Brooks AJ, Behncken SN, Kerr LM, Millard K, Palethorpe K, Nielsen K, Clyde-Smith J, Hancock JF, Waters MJ.; ''An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway.''; PubMed Europe PMC
  5. Kim B, Cheng HL, Margolis B, Feldman EL.; ''Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.''; PubMed Europe PMC
  6. Silva CM, Day RN, Weber MJ, Thorner MO.; ''Human growth hormone (GH) receptor is characterized as the 134-kilodalton tyrosine-phosphorylated protein activated by GH treatment in IM-9 cells.''; PubMed Europe PMC
  7. Postel-Vinay MC, Finidori J.; ''Growth hormone receptor: structure and signal transduction.''; PubMed Europe PMC
  8. Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel WJ, Barnard R, Waters MJ, Wood WI.; ''Growth hormone receptor and serum binding protein: purification, cloning and expression.''; PubMed Europe PMC
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  10. Brooks AJ, Waters MJ.; ''The growth hormone receptor: mechanism of activation and clinical implications.''; PubMed Europe PMC
  11. Ross RJ, Esposito N, Shen XY, Von Laue S, Chew SL, Dobson PR, Postel-Vinay MC, Finidori J.; ''A short isoform of the human growth hormone receptor functions as a dominant negative inhibitor of the full-length receptor and generates large amounts of binding protein.''; PubMed Europe PMC
  12. Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE, Lavan BE.; ''Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells.''; PubMed Europe PMC
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  15. Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA.; ''Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity.''; PubMed Europe PMC
  16. de Vos AM, Ultsch M, Kossiakoff AA.; ''Human growth hormone and extracellular domain of its receptor: crystal structure of the complex.''; PubMed Europe PMC
  17. Rowland JE, Lichanska AM, Kerr LM, White M, d'Aniello EM, Maher SL, Brown R, Teasdale RD, Noakes PG, Waters MJ.; ''In vivo analysis of growth hormone receptor signaling domains and their associated transcripts.''; PubMed Europe PMC
  18. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K.; ''The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation.''; PubMed Europe PMC
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History

View all...
CompareRevisionActionTimeUserComment
101550view11:41, 1 November 2018ReactomeTeamreactome version 66
101085view21:24, 31 October 2018ReactomeTeamreactome version 65
100614view19:58, 31 October 2018ReactomeTeamreactome version 64
100165view16:43, 31 October 2018ReactomeTeamreactome version 63
99715view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99292view12:46, 31 October 2018ReactomeTeamreactome version 62
93823view13:38, 16 August 2017ReactomeTeamreactome version 61
93372view11:21, 9 August 2017ReactomeTeamreactome version 61
87142view18:53, 18 July 2016MkutmonOntology Term : 'growth hormone signaling pathway' added !
86457view09:18, 11 July 2016ReactomeTeamreactome version 56
83058view09:48, 18 November 2015ReactomeTeamVersion54
81367view12:53, 21 August 2015ReactomeTeamVersion53
76835view08:06, 17 July 2014ReactomeTeamFixed remaining interactions
76539view11:51, 16 July 2014ReactomeTeamFixed remaining interactions
75872view09:52, 11 June 2014ReactomeTeamRe-fixing comment source
75572view10:38, 10 June 2014ReactomeTeamReactome 48 Update
74927view13:45, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74571view08:36, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADAM17ProteinP78536 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated

cytokine-like hormone receptors,

p-Y1007-JAK2
ComplexR-HSA-1364054 (Reactome)
Activated

cytokine-like

hormone receptors
ComplexR-HSA-1364055 (Reactome)
CIS, SOCS1-3ComplexR-HSA-1169189 (Reactome)
CISH ProteinQ9NSE2 (Uniprot-TrEMBL)
CSH1 ProteinP0DML2 (Uniprot-TrEMBL)
GH1 ProteinP01241 (Uniprot-TrEMBL) Growth hormone is typically used to refer to the endogenous hormone - somatotropin is reserved for synthetic hormone produced by recombinant technology.
GH2 ProteinP01242 (Uniprot-TrEMBL)
GHBP:GHComplexR-HSA-1362492 (Reactome)
GHBP:GHRComplexR-HSA-1362481 (Reactome)
GHR activated ProteinP10912 (Uniprot-TrEMBL)
GHR(19-256) ProteinP10912 (Uniprot-TrEMBL)
GHR(19-256)ProteinP10912 (Uniprot-TrEMBL)
GHR(19-638) ProteinP10912 (Uniprot-TrEMBL)
GHR(19-638)ProteinP10912 (Uniprot-TrEMBL)
GHR(257-638)ProteinP10912 (Uniprot-TrEMBL)
Growth

Hormone: Activated Growth Hormone

Receptor:p(Y1007)-JAK2 dimer:STAT1/STAT3
ComplexR-HSA-1169146 (Reactome)
Growth

Hormone: Activated Growth Hormone

Receptor:p(Y1007)-JAK2 dimer:p(Y701)-STAT1/p(Y705)-STAT3
ComplexR-HSA-1169186 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:CIS/SOCS1-3
ComplexR-HSA-1169217 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP1
ComplexR-HSA-1169243 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP2
ComplexR-HSA-1169227 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SOCS
ComplexR-HSA-1169198 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
ComplexR-HSA-1168898 (Reactome)
Growth

Hormone:Growth Hormone Receptor-JAK2

dimer:LYN
ComplexR-HSA-1168921 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:STAT5
ComplexR-HSA-1168902 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:p-STAT5
ComplexR-HSA-1168901 (Reactome)
Growth Hormone:p(Y332,487,627)-Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SHP2ComplexR-HSA-1169233 (Reactome)
Growth Hormone Receptor-JAK2 dimerComplexR-HSA-982764 (Reactome)
Growth Hormone Receptor:JAK2ComplexR-HSA-982774 (Reactome)
Growth Hormone R-HSA-982814 (Reactome)
Growth Hormone:

Activated Growth Hormone

Receptor-JAK2 dimer
ComplexR-HSA-1168384 (Reactome)
Growth Hormone:

Activated Growth Hormone Receptor-

p(Y1007)-JAK2 dimer
ComplexR-HSA-1168856 (Reactome)
Growth Hormone:

Growth Hormone

Receptor-JAK2 dimer
ComplexR-HSA-982813 (Reactome)
Growth Hormone:

Tyrosine phosphorylated Growth Hormone Receptor-JAK2

dimer:SHP1
ComplexR-HSA-1169239 (Reactome)
Growth Hormone:

Tyrosine phosphorylated Growth Hormone Receptor-JAK2

dimer:SHP2
ComplexR-HSA-1169221 (Reactome)
Growth HormoneComplexR-HSA-982814 (Reactome)
Growth hormone oligomerR-HSA-982799 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
IRS1 ProteinP35568 (Uniprot-TrEMBL)
IRS1,2ComplexR-HSA-198273 (Reactome) The proteins mentioned here are examples of IRS family members acting as indicated for IRS.
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2ProteinO60674 (Uniprot-TrEMBL)
LYN ProteinP07948 (Uniprot-TrEMBL)
LYNProteinP07948 (Uniprot-TrEMBL)
MAPK1 ProteinP28482 (Uniprot-TrEMBL)
MAPK3 ProteinP27361 (Uniprot-TrEMBL)
MAPKsComplexR-HSA-169291 (Reactome)
PRL ProteinP01236 (Uniprot-TrEMBL)
PRLR

ligands:Activated PRLR:JAK2

dimer:SH2B1 beta
ComplexR-HSA-1675475 (Reactome)
PRLR ProteinP16471 (Uniprot-TrEMBL)
PTPN1 ProteinP18031 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SH2B1-2 ProteinQ9NRF2-2 (Uniprot-TrEMBL)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS2 ProteinO14508 (Uniprot-TrEMBL)
SOCS3 ProteinO14543 (Uniprot-TrEMBL)
SOCSComplexR-HSA-1169199 (Reactome)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT1, STAT3ComplexR-HSA-1112559 (Reactome)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5A,STAT5BComplexR-HSA-452094 (Reactome)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
p-5Y-GHR(19-638) ProteinP10912 (Uniprot-TrEMBL)
p-STAT5 dimerComplexR-HSA-507919 (Reactome)
p-STAT5 dimerComplexR-HSA-508012 (Reactome)
p-STAT5A, p-STAT5BComplexR-HSA-507929 (Reactome)
p-T,Y MAPKsComplexR-HSA-169289 (Reactome)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-Y-IRS1 ProteinP35568 (Uniprot-TrEMBL)
p-Y-IRS1,p-Y-IRS2ComplexR-HSA-112322 (Reactome)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y332,Y487,Y627-GHR(19-638) ProteinP10912 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y701-STAT1 ProteinP42224 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM17mim-catalysisR-HSA-1168777 (Reactome)
ADPArrowR-HSA-1168394 (Reactome)
ADPArrowR-HSA-1168423 (Reactome)
ADPArrowR-HSA-1168459 (Reactome)
ADPArrowR-HSA-1168767 (Reactome)
ADPArrowR-HSA-982807 (Reactome)
ADPArrowR-HSA-982810 (Reactome)
ATPR-HSA-1168394 (Reactome)
ATPR-HSA-1168423 (Reactome)
ATPR-HSA-1168459 (Reactome)
ATPR-HSA-1168767 (Reactome)
ATPR-HSA-982807 (Reactome)
ATPR-HSA-982810 (Reactome)
Activated

cytokine-like hormone receptors,

p-Y1007-JAK2
ArrowR-HSA-982810 (Reactome)
Activated

cytokine-like

hormone receptors
R-HSA-982810 (Reactome)
CIS, SOCS1-3R-HSA-1168809 (Reactome)
GHBP:GHArrowR-HSA-1362485 (Reactome)
GHBP:GHRArrowR-HSA-1362465 (Reactome)
GHBP:GHRTBarR-HSA-982775 (Reactome)
GHR(19-256)ArrowR-HSA-1168777 (Reactome)
GHR(19-256)R-HSA-1362465 (Reactome)
GHR(19-256)R-HSA-1362485 (Reactome)
GHR(19-638)ArrowR-HSA-1168789 (Reactome)
GHR(19-638)R-HSA-1168777 (Reactome)
GHR(19-638)R-HSA-1168789 (Reactome)
GHR(19-638)R-HSA-1362465 (Reactome)
GHR(19-638)R-HSA-982792 (Reactome)
GHR(257-638)ArrowR-HSA-1168777 (Reactome)
Growth

Hormone: Activated Growth Hormone

Receptor:p(Y1007)-JAK2 dimer:STAT1/STAT3
ArrowR-HSA-1168768 (Reactome)
Growth

Hormone: Activated Growth Hormone

Receptor:p(Y1007)-JAK2 dimer:STAT1/STAT3
R-HSA-1168767 (Reactome)
Growth

Hormone: Activated Growth Hormone

Receptor:p(Y1007)-JAK2 dimer:STAT1/STAT3
mim-catalysisR-HSA-1168767 (Reactome)
Growth

Hormone: Activated Growth Hormone

Receptor:p(Y1007)-JAK2 dimer:p(Y701)-STAT1/p(Y705)-STAT3
ArrowR-HSA-1168767 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:CIS/SOCS1-3
ArrowR-HSA-1168809 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP1
ArrowR-HSA-1168839 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP1
R-HSA-1169188 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP1
mim-catalysisR-HSA-1169188 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP2
ArrowR-HSA-1168445 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP2
R-HSA-1169192 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP2
R-HSA-1169210 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP2
mim-catalysisR-HSA-1169192 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SHP2
mim-catalysisR-HSA-1169210 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:SOCS
ArrowR-HSA-1168813 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
ArrowR-HSA-1168894 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
ArrowR-HSA-982807 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
R-HSA-1168393 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
R-HSA-1168445 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
R-HSA-1168809 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
R-HSA-1168813 (Reactome)
Growth

Hormone: Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer
R-HSA-1168839 (Reactome)
Growth

Hormone:Growth Hormone Receptor-JAK2

dimer:LYN
ArrowR-HSA-1168456 (Reactome)
Growth

Hormone:Growth Hormone Receptor-JAK2

dimer:LYN
mim-catalysisR-HSA-1168459 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:STAT5
ArrowR-HSA-1168393 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:STAT5
R-HSA-1168394 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:STAT5
mim-catalysisR-HSA-1168394 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:p-STAT5
ArrowR-HSA-1168394 (Reactome)
Growth

Hormone:Tyrosine phosphorylated Growth Hormone

Receptor-p(Y1007)-JAK2 dimer:p-STAT5
R-HSA-1168894 (Reactome)
Growth Hormone:p(Y332,487,627)-Growth Hormone Receptor-p(Y1007)-JAK2 dimer:SHP2ArrowR-HSA-1169192 (Reactome)
Growth Hormone Receptor-JAK2 dimerArrowR-HSA-982775 (Reactome)
Growth Hormone Receptor-JAK2 dimerR-HSA-982778 (Reactome)
Growth Hormone Receptor:JAK2ArrowR-HSA-982792 (Reactome)
Growth Hormone Receptor:JAK2R-HSA-982775 (Reactome)
Growth Hormone:

Activated Growth Hormone

Receptor-JAK2 dimer
ArrowR-HSA-982768 (Reactome)
Growth Hormone:

Activated Growth Hormone Receptor-

p(Y1007)-JAK2 dimer
R-HSA-1168768 (Reactome)
Growth Hormone:

Activated Growth Hormone Receptor-

p(Y1007)-JAK2 dimer
R-HSA-982807 (Reactome)
Growth Hormone:

Activated Growth Hormone Receptor-

p(Y1007)-JAK2 dimer
mim-catalysisR-HSA-1168423 (Reactome)
Growth Hormone:

Activated Growth Hormone Receptor-

p(Y1007)-JAK2 dimer
mim-catalysisR-HSA-982807 (Reactome)
Growth Hormone:

Growth Hormone

Receptor-JAK2 dimer
ArrowR-HSA-982778 (Reactome)
Growth Hormone:

Growth Hormone

Receptor-JAK2 dimer
R-HSA-1168456 (Reactome)
Growth Hormone:

Growth Hormone

Receptor-JAK2 dimer
R-HSA-982768 (Reactome)
Growth Hormone:

Tyrosine phosphorylated Growth Hormone Receptor-JAK2

dimer:SHP1
ArrowR-HSA-1169188 (Reactome)
Growth Hormone:

Tyrosine phosphorylated Growth Hormone Receptor-JAK2

dimer:SHP2
ArrowR-HSA-1169210 (Reactome)
Growth HormoneR-HSA-1362485 (Reactome)
Growth HormoneR-HSA-982765 (Reactome)
Growth HormoneR-HSA-982778 (Reactome)
Growth hormone oligomerArrowR-HSA-982765 (Reactome)
H2OR-HSA-1169192 (Reactome)
H2OR-HSA-1169210 (Reactome)
IRS1,2R-HSA-1168423 (Reactome)
JAK2R-HSA-982792 (Reactome)
LYNR-HSA-1168456 (Reactome)
MAPKsR-HSA-1168459 (Reactome)
PRLR

ligands:Activated PRLR:JAK2

dimer:SH2B1 beta
ArrowR-HSA-982810 (Reactome)
PTPN1R-HSA-1168445 (Reactome)
PTPN6R-HSA-1168839 (Reactome)
PiArrowR-HSA-1169188 (Reactome)
PiArrowR-HSA-1169192 (Reactome)
PiArrowR-HSA-1169210 (Reactome)
R-HSA-1168393 (Reactome) JAK2 is required for GH-mediated phosphorylation of STATs 1,3,5A and 5B (Smit et al.1996). Some STAT activation may be mediated by direct association of JAK and STAT but maximal activation requires binding of STATs to phosphorylated tyrosines of the receptor (Smit et al. 1996, Lichanska & Waters 2006). Studies using mouse GHR truncated at K391, equivalent to human K380, suggest that STAT5 signaling is mediated by distal tyrosines, with 70% of the signaling lost if the receptor is truncated at P569, equivalent to human P558 (Rowland et al. 2005). Wang et al. (1996) using the porcine receptor found that phosphorylation at any one of the positions Y487, Y534, Y566 or Y627 (numbering identical in humans) was sufficient to allow STAT5 phosphorylation. Smit et al. (1996) identified mouse residues Y341 (human Y332) and Y346 (not conserved in human) as required for STAT1, 3, and maximal STAT5 activation.
R-HSA-1168394 (Reactome) Stat5 tyrosine phosphorylation was seen in response to GH in CHO cells expressing mouse GHR forms capable of binding JAK2 (Smit et al. 1996). Similar results were obtained using the porcine receptor (Wang et al. 1996). Thus Jak2 phosphorylates Stat5, the phosphorylated monomers form dimers and translocate to the nucleus (Darnell et al. 1994).
R-HSA-1168423 (Reactome) GH has short term effects that mimic the actions of insulin in tissues that have been deprived of GH, including increased amino acid transport, glucose transport, and lipogenesis (Davidson 1987). GH and insulin have overlapping signaling pathways (Dominici et al. 2005). GH stimulates tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1) (Souza et al. 1994, Thirone et al. 1999), and IRS-2 (Argetsinger et al. 1996, Thirone et al. 1999), although more modestly than insulin or IGF-1. Tyrosyl phosphorylation of IRS-1 and IRS-2 in response to insulin provides binding sites for specific proteins containing SH2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), tyrosine phosphatase SHP2, and Grb2. This is one of several mechanisms proposed to explain the stimulatory effect of GH on the PI3-kinase/Akt pathway (Jin et al. 2008). GH promotes the binding of the 85-kDa regulatory subunit of PI3K to IRS-1 and IRS-2 in cultured cells (Ridderstrale et al. 1995, Argetsinger et al. 1995, 1996). Studies using truncated or mutated GHRs suggest that tyrosyl phosphorylation of IRS-1, IRS-2, and Shc is dependent on JAK2 activation (Argetsinger et al. 1995, 1996, VanderKuur et al. 1995). Despite a strong correlation between JAK2 activation and IRS phosphorylation it is not clear whether there is a direct association. JAK2 has been reported to interact directly with IRS in response to angiotensin II (Velloso et al. 1996) but also reported to interact indirectly via SH2B in response to leptin (Duan et al.2004).
R-HSA-1168445 (Reactome) PTP1B has been shown to associate with GH-dependent phosphorylated GHR and induce its dephosphorylation (Pasquali et al. 2003). It can also dephosphorylate JAK2 (Gu et al. 2003). Both have the effect of reducing JAK signaling.
R-HSA-1168456 (Reactome) There is accumulating evidence that GH signalling utilises a Src family tyrosine kinase independently of JAK2, and that this is linked to activation of extracellular regulated kinases (ERKs) 1 and 2 (p44/42 MAPK). The relative strengths of these signaling pathways probably depends on cell type and may be mediated by conformational changes that are a consequence of ligand binding (Rowlinson et al. 2007). In NIH-3T3 cells GH activated c-Src, which in turn activated ERK1/2 via a pathway involving the activation of the Ras-like small GTPases RalA and RalB, leading to Elk-1 mediated transcription (Zhu et al. 2002). JAK2 and c-Src were both found to activate the Ras-like small GTPases Rap1 and Rap2 which inhibit RalA mediated activation of ERK1/2 (Ling et al. 2003). Src kinase inhibition was found to block ERK activation by GH. The major contributing kinase was identified as Lyn, which was found to co-immunoprecipitate with GHR and bind to the proximal 150 residues of the cytoplasmic domain (Rowlinson et al. 2007).
R-HSA-1168459 (Reactome) The activation of Lyn by GHR is thought to indirectly activate ERK. Mutations of GHR predicted to disable a conformational change brought about by GH binding impaired ERK signaling but not JAK2/STAT5 signaling. ERK signaling was demonstrated to involve the Src family kinase Lyn (Rowlinson et al. 2008) and suggested to involve Src kinase dependent activation of Phospholipase C gamma and thereby Ras, similar to a mechanism proposed by Bivona et al. (2003). ERK activation mechanisms involving Src kinases and PLCgamma have been reported for the erythropoietin, thrombopoietin and prolactin receptors (Brooks & Waters 2010).
R-HSA-1168767 (Reactome) GH stimulated tyrosyl phosphorylation of Stats 1, 3, and 5 in CHO cells expressing GHR constructs that bind JAK2 but not in CHO cells expressing GHR constructs that do not bind JAK2 (Smit et al. 1996). STAT5 phosphorylation was greatly reduced in GHR mutants with the distal region of the cytoplasmic tail removed and by mutation of distal GHR tyrosine residues to phenylalanine but this had no effect on STAT1/STAT3 phosphorylation, suggesting that the latter interact with JAK2 directly.
R-HSA-1168768 (Reactome) JAK2 is believed to bind STAT1 and STAT3 directly in response to GH, as opposed to STAT5 which binds to phosphorylated tyrosine residues in the distal portion of the GHR cytoplasmic region (Smit et al. 1996). When associated with the prolactin receptor JAK2 is able to bind STAT1, STAT3 and STAT5 (DaSilva et al. 1996). Smit et al. identified mouse GHR residues Y341 (human Y332) and Y346 (not conserved in human) as required for STAT1, 3, and maximal STAT5 activation.
R-HSA-1168777 (Reactome) Approximately half of circulating GH is bound to Growth Hormone Binding Protein ((GHBP) Herington et al. 1986), a soluble fragment of the Growth Hormone Receptor (Baumann et al. 1986) formed when the extracellular region is proteolytically cleaved (Leung et al. 1987). This cleavage is mediated by metalloproteases such as TACE (ADAM17, Zhang et al. 2000). The membrane-bound remnant is subsequently degraded by the gamma-secretase complex (Cowan et al. 2005).
R-HSA-1168789 (Reactome) Cell surface levels of GHR are the primary determinant of GH responsiveness. This is modulated partly by endocytosis and lysosomal degradation. This downregulation is strongly inhibited by the association of JAK2 with the receptor, and by GH if JAK2 is prevented from signaling, but markedly enhanced by GH if JAK2 is kinase active. GH down-regulation also requires GHR tyrosine phosphorylation (Deng et al. 2007) and is believed to be mediated by GHR ubiquitination and proteasomal degradation.
R-HSA-1168809 (Reactome) Suppressor of Cytokine Signaling (SOCS) proteins inhibit the GH signal; SOCS2 null mice exhibit giantism (Greenhalgh et al. 2005). Suppressor of Cytokine Signaling (SOCS)1-3, and the realted Cytokine-inducible SH2-containing protein (CIS) all bind tyrosine-phosphorylated GHR; SOCS1 can also binds GHR in the absence of tyrosine phosphorylation (Ram & Waxman 1999, Hansen et al. 1999). SOCS3 binding has been mapped to phosphorylated tyrosines Y338, Y333 (Ram & Waxman 1999), and Y487 (Hansen et al. 1999) in the membrane proximal region of the receptor while SOCS2 and CIS bind to residues Y487 and Y595 (Uyttendaele et al. 2007). SOCS2/3/CIS may compete with STAT5 for GHR binding at these sites but in the case of SOCS3 also appears to act by inhibiting JAK2 directly (Yasukawa et al. 1999).
R-HSA-1168813 (Reactome) SOCS1 can bind JAK2 and inhibit JAK kinase activity (Yasukawa et al. 1999). SOCS3 also inhibits JAK2 kinase activity (Sasaki et al. 1999) while all of SOCS1 -3 and CIS inhibit GHR signaling (Ram & Waxman 1999, Nicholson et al. 2000). This is not thought to be simply the outcome of binding competition between SOCS and STAT5, but a direct action of SOCS on JAK2 (Ram & Waxman 1999). Although SOCS are known to be ubiquitin ligases (Kamura et al. 2004), ubiquitin ligase activity on JAK2 or GHR has not been demonstrated and a role for SOCS in the ubiquitination of these proteins has been questioned (Flores-Morales et al. 2006). An alternative model suggested by the observation that SOCS3 strongly inhibits JAK2 only in the presence of GHR proposes that SOCS serve as an inhibitory 'bridge' by binding simultaneously to GHR and JAK2 (Ram & Waxman 1999).
R-HSA-1168839 (Reactome) SHP1 binds GH-activated JAK2 and controls the duration of GH-dependent JAK2 phosphorylation in the liver, consequently hepatic GH signaling is prolonged in mice lacking SHP1 (Hackett et al. 1999).
R-HSA-1168894 (Reactome) Deletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believed to occur following release of the phosphorylated monomers from the receptor complex and is typically represented in this manner (e.g. Turkson & Jove 2000).
R-HSA-1169188 (Reactome) SHP1 (PTPN6) dephosphorylates GH-activated JAK2, limiting the duration of signaling (Hackett et al. 1999).
R-HSA-1169192 (Reactome) PTP1B induces the dephosphorylation of GHR (Pasquali et al. 2003).
R-HSA-1169210 (Reactome) PTP1B dephosphorylates JAK2 (Gu et al. 2003), limiting ligand-dependent signaling.
R-HSA-1362465 (Reactome) GHBP, the ectodomain of GHR cleaved from membrane-bound GHR can form a heterodimer with GHR. This is not capable of signaling and may be a negative regulatory influence. GHBP can also inhibit signaling by competing with the full length receptor for GH binding.
R-HSA-1362485 (Reactome) GHBP is the ectodomain of GHR, cleaved from membrane-bound GHR in man and rabbits, while in rodents it is derived from an alternatively spliced mRNA. GHBP circulates in nanomolar concentrations, sufficient to complex approximately 50% of plasma GH (Baumann et al. 1988). GHBP can compete for GHR binding, inhibiting GHR signaling (Lim et al. 1990), and generates 'unproductive' heterodimers with GHR at the cell surface (Ross et al. 1997), but GHBP can also increase GH biological activity by prolonging its half-life (Baumann et al. 1987). The net effect of GHBP may depend on the relative concentrations of circulating GH and GHBP (Lim et al. 1990, Barnard & Waters 1997), the overall effect is postulated to be stabilization of GH signaling (Veldhuis et al. 1993). GHBP appears to be positively linked to GH action. It has been suggested that plasma GHBP levels reflect tissue concentrations of GHR, but this remains to be proven.
R-HSA-452102 (Reactome) Phosphorylated STAT5A and STAT5B form homodimers and heterodimers in the cytosol (Gaffen et al. 1996, Rosenthal et al. 1997, also inferred from mouse homologs). Phosphorylation of a critical tyrosine residue in the SH domain (Y694 in STAT5A and Y699 in STAT5B) and intramolecular interactions between hydrophobic residues in the SH domain are required for dimerization (inferred from mouse homologs).
R-HSA-507937 (Reactome) Interleukin-7 (IL7)-activated Signal transducer and activator of transcription 5A or 5B (typically referred to as STAT5) is recruited rapidly to the promoters of IL7-regulated genes (Ye et al. 2001, Stanton & Brodeur 2005).
R-HSA-982765 (Reactome) Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms. The peptide is encoded by 2 genes, GH1 and GH2, both give rise to multiple variant forms. Post-translational modification including oligomerization increases the variation (Baumann 2009). Approximately 14% of circulating human Growth Hormone (GH) is in dimer or oligomer form, this number varying from 0 to 100% (Kublickas et al. 2006). The biological activity of these oligomeric forms is variably diminished when compared to the monomer (Baumann 2009).
R-HSA-982768 (Reactome) Classical models of GHR activation suggest that GH binds sequentially to two GHR molecules, leading to receptor dimerization and activation. More recently, evidence from FRET, BRET, Co-IP (Brown et al. 2005) and molecular simulations (Poger & Mark 2010) suggest that dimerization occurs before ligand binding, and that activation is a consequence of conformational changes caused by ligand binding, namely a relative rotation of the receptor dimer so that the catalytic domains of JAK2 molecules bound to the cytoplasmic tails are brought into close proximity and are consequently able to phosphorylate each other (Rowlinson et al. 2008). Realignment of the receptor subunits and consequent JAK2 activation is supported by crystal structures of the related erythropoietin receptor (Livnah et al. 1999); similar proposals have been made for many receptors, including the prolactin and erythropoietin receptors (Brooks & Waters 2010).
R-HSA-982775 (Reactome) The growth hormone receptor forms dimers (Cunningham et al. 1991) that subsequently signal via JAK2 (Argetsinger et al. 1993). Early studies suggested that dimerization occured following ligand binding, but it is now generally accepted that dimerization is independent of ligand binding and involves the transmembrane and juxtamembrane domains (van den Eijnden et al. 2006, Brown et al. 2005).
R-HSA-982778 (Reactome) The growth hormone receptor (GHR) belongs to the superfamily of transmembrane proteins that includes the prolactin receptor and a number of class 1 cytokine receptors. It exists in two forms, full-length membrane-bound receptor with a single transmembrane region, and growth hormone binding protein (GHBP), a shorter soluble form corresponding to the extracellular domain of the full-length receptor. In rodents GHBP is encoded by a specific mRNA variant while in humans it results from proteolytic cleavage of the membrane receptor by a metalloprotease. The classical view is that growth hormone sequentially binds 2 molecules of GHR inducing dimerization, but it is now widely accepted that GHR dimers exist prior to ligand binding (Poger & Mark 2010).
R-HSA-982792 (Reactome) JAKs bind to the box1 motif (residues 297-305) of the Growth Hormone Receptor (GHR) (Argetsinger et al. 1993), a proline-rich region just inside the cell membrane. Binding is mediated largely by the JAK N-terminal FERM domain (Frank et al. 1995, He et al. 2003). JAK 2 binding enhances the stability of GHR (He et al. 2005).
R-HSA-982807 (Reactome) Activated JAK2 phosphorylates multiple tyrosine residues on GHR (Argetsinger et al. 1993, VanderKuur et al. 1994) including Y332 (VanderKuur 1995), Y487, Y534, Y566, and Y627 (Wang et al. 1996). Wang et al. using the porcine receptor found that phosphorylation at any of the positions they examined (all conserved in humans) was sufficient for STAT5 phosphorylation. While STAT5 activation requires phosphorylation of the distal region of GHR, this has no effect on STAT1 or STAT3 activation (Yi et al. 1996) suggesting different mechanisms. Mutation of Y332 to F in a truncated form of GHR with only the first 54 residues of the cytoplasmic domain had no effect on JAK2 activation or cell proliferation presumed to be mediated by ERK (Wang et al. 1995) so the significance of phosphorylation at this position is unclear. SHP2 binds to Y595 of rat GHR (identical numbering in humans) and to a lesser extent Y487; mutation of these residues impairs the association (Stofega et al. 2000). SOCS3 binds to rat GHR Y333 (equivalent of human Y332), Y338 (not conserved in humans) (Ram & Waxman 1999) and Y487 (Hansen et al. 1999).

SOCS-1 has been implicated as a direct inhibitor of JAK kinases (Yasukawa et al. 1999).

This reaction represents the phosphorylation of all GHR tyrosines known to be phosphorylated by JAK2.
R-HSA-982810 (Reactome) Similar models explain JAK activation by the cytokine-like hormone receptors (GHR and PRLR) and interleukin receptors. JAK2 activation is believed to occur as mutual transactivation whereby JAK2 bound to one receptor chain phosphorylates JAK2 bound to the other receptor chain in the dimeric receptor. Transactivation is widely accepted (Herrington & Carter-Su 2001) having been originally proposed in the 1990's (Quelle et al. 1994, Hou et al. 2002). JAK phosphorylation is thought to lock the kinase domain in an active state; prior to this JAK2 is held in an inactive state by interactions between its kinase and pseudokinase domains (Giordanetto & Kroemer 2002). Although there are structures of JAK kinase domains (e.g. Lucet et al. 2006), no complete JAK structures are available and the activation mechanism remains poorly understood (Brooks & Waters 2010). The trigger for JAK activation is believed to be a conformational change in the receptor when ligand is bound, leading to a rotation of the cytoplasmic regions which brings the catalytic domains of bound JAK2 molecules into close proximity and frees them from inhibition by the pseudokinase domains. Supporting observations for cytokine-like hormone receptors include: JAK2 becomes tyrosine phosphorylated as a consequence of GHR activation by GH (Argetsinger et al. 1993); JAK2 is activated following PRLR activation (Campbell et al. 1994, Rui et al. 1994); forced dimerization of GH receptor domains is sufficient to activate signaling (Behncken et al. 2000); phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006); JAK autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the Y1007 phosphorylation is represented in this reaction.
SOCSR-HSA-1168813 (Reactome)
STAT1, STAT3R-HSA-1168768 (Reactome)
STAT5A,STAT5BR-HSA-1168393 (Reactome)
p-STAT5 dimerArrowR-HSA-452102 (Reactome)
p-STAT5 dimerArrowR-HSA-507937 (Reactome)
p-STAT5 dimerR-HSA-507937 (Reactome)
p-STAT5A, p-STAT5BArrowR-HSA-1168894 (Reactome)
p-STAT5A, p-STAT5BR-HSA-452102 (Reactome)
p-T,Y MAPKsArrowR-HSA-1168459 (Reactome)
p-Y-IRS1,p-Y-IRS2ArrowR-HSA-1168423 (Reactome)
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