Signaling by Erythropoietin (Homo sapiens)

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1, 6, 7, 15, 17...22, 23, 31, 508, 169, 10, 18, 29, 36...20, 312838, 42, 4631, 32, 50226, 5342, 4920, 31, 4120, 3122, 31, 5018, 312, 4416, 27, 4835, 37, 404, 4214, 32141449, 523, 5, 25, 28, 30...extracellular regioncytosolSTAT5A IRS2 ATPGRB2-1 p-Y-IRS2 IRS2 p-CRKL EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-PLCG1,2ATPPLCG2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1p-12Y-JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1:PI3Kp-8Y-EPOR p-Y-PLCG2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:p-Y-VAV1p-8Y-EPOR PI(4,5)P2p-8Y-EPOR GAB1EPO EPOR p-12Y-JAK2 IRS2 GTP p-8Y-EPOR EPO PIK3R5 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1,p-Y-VAV1p-Y694-STAT5A PIK3R1 LYN PIK3CG PIK3CD PIK3CG RAPGEF1 RAPGEF1 PI3K alpha, gammaEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:STAT5p-12Y-JAK2 I(1,4,5)P3KRAS CRKL:RAPGEF1IRS2 EPOR IRS2 PI(4,5)P2NRAS p-Y-SHC1 CRKL p-12Y-JAK2 p-12Y-JAK2 p-12Y-JAK2 IRS2 IRS2 IRS2 p-8Y-EPOR p-12Y-JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1PIK3R1 SHC1p-8Y-EPOR DAGsp-8Y-EPOR GDP RAPGEF1 PIK3CD EPO:EPOR:p-Y12-JAK2:LYN:IRS2p-12Y-JAK2 p-8Y-EPOR IRS2 IRS2 LYN p-8Y-EPOR LYN p-Y699-STAT5B PIK3R5 SOS1 p-Y694-STAT5A PIK3CD p-CRKL IRS2 p-Y-SHC1 p-Y-IRS2 p-12Y-JAK2 p-Y-IRS2 EPOR:JAK2:LYN:IRS2p-CRKL EPO LYN p-STAT5A, p-STAT5Bp-Y-GAB1 RAPGEF1 PIK3R1 PIK3CD p-CRKL p-12Y-JAK2 EPO STAT5B IRS2 ADPPLC gamma1,2GRB2-1 IRS2 p-8Y-EPOR EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1p-Y-SHC1 PIK3CG CRKL PIK3CB p-Y-PLCG1 p-12Y-JAK2 ADPLYN ADPEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:VAV1PLCG1 IRS2 p-8Y-EPOR p-Y-VAV1 PIK3CB EPO EPO LYN p-8Y-EPOR H2Op-12Y-JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:SHC1EPO p-12Y-JAK2 p-12Y-JAK2 LYN ATPEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PLCG1,2ATPLYN ATPEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PI3KVAV1 PIK3CB VAV1 GRB2-1 EPO p-8Y-EPOR LYN LYN p-Y-GAB1 IRS2 JAK2 LYN EPOR EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:GAB1PIK3CA EPO PIK3CB PIK3CA p-8Y-EPOR PLCG1 STAT5B ATPEPO JAK2 PIK3R1 GRB2-1:SOS1EPO EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-STAT5EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:CRKL:RAPGEF1KRAS EPO IRS2 EPO RAPGEF1 EPO RAPGEF1 STAT5A,STAT5BEPO ATPEPO GRB2-1 LYN ATPSOS1 ADPEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2NRAS LYN p-8Y-EPOR PIK3CG IRS2 LYN p-Y699-STAT5B p-12Y-JAK2 GAB1 EPOGRB2-1 PIK3CD LYN GTPADPPIK3R5 IRS2 p-8Y-EPOR GDPp21 RAS:GDPLYN p-Y-VAV1 p-12Y-JAK2 LYN SOS1 EPO PIK3CA PIK3R1 p-12Y-JAK2 PIK3CB p-12Y-JAK2 PLCG2 PIK3R5 ATPADPRAPGEF1 STAT5A IRS2 EPO PIK3CA LYN EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1PIK3CA p-8Y-EPOR PIK3CG ATPLYN LYN ADPHRAS p-8Y-EPOR IRS2 p-8Y-EPOR p-12Y-JAK2 EPO ADPGRB2-1 p-Y-SHC1 p21 RAS:GTPp-CRKL EPO:EPOR:JAK2:LYN:IRS2p-Y-SHC1 RAPGEF1 p-CRKL PI(3,4,5)P3PIK3R5 EPO EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2:PI3KPI3K bound to EPORADPp-Y-GAB1 HRAS ADPIRS2 EPO LYN SHC1 EPO p-CRKL LYN p-12Y-JAK2 GRB2-1:VAV1LYN p-8Y-EPOR p-12Y-JAK2 RAPGEF1 212, 13212, 13333112, 1312, 1318, 20, 4112, 133312, 13212, 133112, 1312, 1312, 1338, 4242, 4912, 1312, 1338, 42, 46212, 13314, 38, 4212, 132212, 1331212, 1312, 1312, 1312, 133112, 1312, 1311, 34, 5421, 23


Erythropoietin (EPO) is a cytokine that serves as the primary regulator of erythropoiesis, the differentiation of erythrocytes from stem cells in the liver of the fetus and the bone marrow of adult mammals (reviewed in Ingley 2012, Zhang et al. 2014, Kuhrt and Wojchowski 2015). EPO is produced in the kidneys in response to low oxygen tension and binds a receptor, EPOR, located on progenitor cells: burst forming unit-erythroid (BFU-e) cells and colony forming unit-erythroid (CFU-e) cells.
The erythropoietin receptor (EPOR) exists in lipid rafts (reviewed in McGraw and List 2017) as a dimer pre-associated with proteins involved in downstream signaling: the tyrosine kinase JAK2, the tyrosine kinase LYN, and the scaffold protein IRS2. Binding of EPO to the EPOR dimer causes a change in conformation (reviewed in Watowich et al. 2011, Corbett et al. 2016) that activates JAK2, which then transphosphorylates JAK2 and phosphorylates the cytoplasmic domain of EPOR. The phosphorylated EPOR serves directly or indirectly as a docking site for signaling molecules such as STAT5, phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phospholipase C gamma (PLCG1, PLCG2), and activators of RAS (SHC1, GRB2:SOS1, GRB2:VAV1).
EPO activates 4 major signaling pathways: STAT5-activated transcription, PI3K-AKT, RAS-RAF-ERK, and PLC-PKC. JAK2-STAT5 activates expression of BCL2L1 (Bcl-xL) and therefore appears to be important for anti-apoptosis. PI3K-AKT appears to be important for both anti-apoptosis and proliferation. The roles of other signaling pathways are controversial but both RAS-RAF-MEK-ERK and PLCgamma-PKC have mitogenic effects. Phosphatases such as SHP1 are also recruited and downregulate the EPO signal.
EPO also has effects outside of erythropoiesis. The EPOR is expressed in various tissues such as endothelium where it can act to stimulate growth and promote cell survival (Debeljak et al. 2014, Kimáková et al. 2017). EPO and EPOR in the neurovascular system act via Akt, Wnt1, mTOR, SIRT1, and FOXO proteins to prevent apoptotic cell injury (reviewed in Ostrowski and Heinrich 2018, Maiese 2016) and EPO may have therapeutic value in the nervous system (Ma et al. 2016). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 9006335
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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  54. Kyono WT, de Jong R, Park RK, Liu Y, Heisterkamp N, Groffen J, Durden DL.; ''Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI).''; PubMed Europe PMC Scholia
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101667view13:47, 1 November 2018DeSlOntology Term : 'erythropoietin signaling pathway' added !
101659view11:51, 1 November 2018ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CRKL ProteinP46109 (Uniprot-TrEMBL)
CRKL:RAPGEF1ComplexR-HSA-9024734 (Reactome)
DAGsMetaboliteCHEBI:18035 (ChEBI)
EPO ProteinP01588 (Uniprot-TrEMBL)
EPO:EPOR:JAK2:LYN:IRS2ComplexR-HSA-9006300 (Reactome)
EPO:EPOR:p-Y12-JAK2:LYN:IRS2ComplexR-HSA-9006305 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:CRKL:RAPGEF1ComplexR-HSA-9024721 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:GAB1ComplexR-HSA-9027237 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PI3KComplexR-HSA-9027263 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PLCG1,2ComplexR-HSA-9027402 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:STAT5ComplexR-HSA-9012638 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:SHC1ComplexR-HSA-9027236 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1,p-Y-VAV1ComplexR-HSA-9029079 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1ComplexR-HSA-9029089 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:VAV1ComplexR-HSA-9029110 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:p-Y-VAV1ComplexR-HSA-9029112 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1ComplexR-HSA-9029088 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1ComplexR-HSA-9024731 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-STAT5ComplexR-HSA-9012641 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1:PI3KComplexR-HSA-9027234 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1ComplexR-HSA-9027235 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-PLCG1,2ComplexR-HSA-9029094 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2ComplexR-HSA-9006301 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2:PI3KComplexR-HSA-9012639 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2ComplexR-HSA-9027242 (Reactome)
EPOProteinP01588 (Uniprot-TrEMBL)
EPOR ProteinP19235 (Uniprot-TrEMBL)
EPOR:JAK2:LYN:IRS2ComplexR-HSA-9006298 (Reactome)
GAB1 ProteinQ13480 (Uniprot-TrEMBL)
GAB1ProteinQ13480 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GRB2-1:VAV1ComplexR-HSA-9029096 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LYN ProteinP07948 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alpha, gammaComplexR-HSA-9012640 (Reactome)
PI3K bound to EPORComplexR-HSA-9027238 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3CG ProteinP48736 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R5 ProteinQ8WYR1 (Uniprot-TrEMBL)
PLC gamma1,2ComplexR-HSA-1169089 (Reactome)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG2 ProteinP16885 (Uniprot-TrEMBL)
RAPGEF1 ProteinQ13905 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5A,STAT5BComplexR-HSA-452094 (Reactome)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-12Y-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-8Y-EPOR ProteinP19235 (Uniprot-TrEMBL)
p-CRKL ProteinP46109 (Uniprot-TrEMBL)
p-STAT5A, p-STAT5BComplexR-HSA-507929 (Reactome)
p-Y-GAB1 ProteinQ13480 (Uniprot-TrEMBL)
p-Y-IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
p-Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-Y-PLCG2 ProteinP16885 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y-VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9006323 (Reactome)
ADPArrowR-HSA-9006332 (Reactome)
ADPArrowR-HSA-9012650 (Reactome)
ADPArrowR-HSA-9021627 (Reactome)
ADPArrowR-HSA-9024726 (Reactome)
ADPArrowR-HSA-9027272 (Reactome)
ADPArrowR-HSA-9027273 (Reactome)
ADPArrowR-HSA-9027425 (Reactome)
ADPArrowR-HSA-9029151 (Reactome)
ADPArrowR-HSA-9029155 (Reactome)
ATPR-HSA-9006323 (Reactome)
ATPR-HSA-9006332 (Reactome)
ATPR-HSA-9012650 (Reactome)
ATPR-HSA-9021627 (Reactome)
ATPR-HSA-9024726 (Reactome)
ATPR-HSA-9027272 (Reactome)
ATPR-HSA-9027273 (Reactome)
ATPR-HSA-9027425 (Reactome)
ATPR-HSA-9029151 (Reactome)
ATPR-HSA-9029155 (Reactome)
CRKL:RAPGEF1R-HSA-9024723 (Reactome)
DAGsArrowR-HSA-9032478 (Reactome)
EPO:EPOR:JAK2:LYN:IRS2ArrowR-HSA-9006325 (Reactome)
EPO:EPOR:JAK2:LYN:IRS2R-HSA-9006332 (Reactome)
EPO:EPOR:JAK2:LYN:IRS2mim-catalysisR-HSA-9006332 (Reactome)
EPO:EPOR:p-Y12-JAK2:LYN:IRS2ArrowR-HSA-9006332 (Reactome)
EPO:EPOR:p-Y12-JAK2:LYN:IRS2R-HSA-9006323 (Reactome)
EPO:EPOR:p-Y12-JAK2:LYN:IRS2mim-catalysisR-HSA-9006323 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:CRKL:RAPGEF1ArrowR-HSA-9024723 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:CRKL:RAPGEF1R-HSA-9024726 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:CRKL:RAPGEF1mim-catalysisR-HSA-9024726 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:GAB1ArrowR-HSA-9027281 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:GAB1R-HSA-9027273 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:GAB1mim-catalysisR-HSA-9027273 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PI3KArrowR-HSA-9027280 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PLCG1,2ArrowR-HSA-9027373 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PLCG1,2R-HSA-9027425 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PLCG1,2mim-catalysisR-HSA-9027425 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:STAT5ArrowR-HSA-9012654 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:STAT5R-HSA-9012650 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:STAT5mim-catalysisR-HSA-9012650 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:SHC1ArrowR-HSA-9027274 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:SHC1R-HSA-9029155 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:SHC1mim-catalysisR-HSA-9029155 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1,p-Y-VAV1mim-catalysisR-HSA-9029158 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1ArrowR-HSA-9029149 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:VAV1ArrowR-HSA-9029150 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:VAV1R-HSA-9029151 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:VAV1mim-catalysisR-HSA-9029151 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:p-Y-VAV1ArrowR-HSA-9029151 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1ArrowR-HSA-9029155 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1R-HSA-9029149 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1R-HSA-9029150 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1ArrowR-HSA-9024726 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1R-HSA-9027274 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-STAT5ArrowR-HSA-9012650 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-STAT5R-HSA-9012651 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1:PI3KArrowR-HSA-9027275 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1ArrowR-HSA-9027273 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1R-HSA-9027275 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-PLCG1,2ArrowR-HSA-9027425 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-PLCG1,2mim-catalysisR-HSA-9032478 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2ArrowR-HSA-9006323 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2ArrowR-HSA-9012651 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2R-HSA-9012654 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2R-HSA-9024723 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2R-HSA-9027272 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2R-HSA-9027280 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2R-HSA-9027281 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2R-HSA-9027373 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2mim-catalysisR-HSA-9027272 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2:PI3KArrowR-HSA-9012657 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2ArrowR-HSA-9027272 (Reactome)
EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2R-HSA-9012657 (Reactome)
EPOR-HSA-9006325 (Reactome)
EPOR:JAK2:LYN:IRS2R-HSA-9006325 (Reactome)
GAB1R-HSA-9027281 (Reactome)
GDPArrowR-HSA-9029158 (Reactome)
GRB2-1:SOS1R-HSA-9029149 (Reactome)
GRB2-1:VAV1R-HSA-9029150 (Reactome)
GTPR-HSA-9029158 (Reactome)
H2OR-HSA-9032478 (Reactome)
I(1,4,5)P3ArrowR-HSA-9032478 (Reactome)
PI(3,4,5)P3ArrowR-HSA-9021627 (Reactome)
PI(4,5)P2R-HSA-9021627 (Reactome)
PI(4,5)P2R-HSA-9032478 (Reactome)
PI3K alpha, gammaR-HSA-9012657 (Reactome)
PI3K alpha, gammaR-HSA-9027275 (Reactome)
PI3K alpha, gammaR-HSA-9027280 (Reactome)
PI3K bound to EPORmim-catalysisR-HSA-9021627 (Reactome)
PLC gamma1,2R-HSA-9027373 (Reactome)
R-HSA-9006323 (Reactome) Phosphorylated JAK2 phosphorylates 8 tyrosine residues in the cytoplasmic tail of EPOR (Dusanter-Fourt et al. 1992, McGraw et al. 2012, and inferred from mouse homologs). The phosphorylated residues then serve as binding sites for scaffold proteins such as CRKL and GAB1 and downstream signaling proteins such as STAT5, phospholipase C, and phosphatidylinositol 3-kinase.
R-HSA-9006325 (Reactome) Extracellular Erythropoietin (EPO) binds the EPO receptor (EPOR) located in the plasma membrane of the target cell (Jones et al. 1990, Syed et al. 1998, Remy et al. 1999, and inferred from mouse homologs). EPOR is a dimer that appears to be preassociated with downstream signaling proteins JAK2 (inferred from mouse homologs) and LYN (Chin et al. 1998, and inferred from mouse homologs) and the scaffold protein IRS2 (Verdier et al. 1997). Binding of EPO to EPOR causes a change in the conformation of the dimer which activates JAK2 (Syed et al. 1998, Remy et al. 1999, Kubatzky et al. 2001).
R-HSA-9006332 (Reactome) Upon binding EPO, the EPOR dimer changes conformation, resulting in activation of JAK2 associated with box 1 and box 2 of the cytoplasmic domain of each EPOR (inferred from mouse homologs). One JAK2 transphosphorylates 12 tyrosine residues of the other JAK2 thereby activating JAK2 to phosphorylate EPOR and other substrates (Arcasoy et al. 1999, Watowich et al. 1999, Erickson-Miller et al. 2000, and inferred from mouse homologs).
R-HSA-9012650 (Reactome) After STAT5 binds the EPO:EPOR complex, phosphorylated JAK2 and LYN phosphorylate STAT5 (STAT5A or STAT5B) (Gouilleux et al. 1995, Pallard et al. 1995, Hoefsloot et al. 1997, Miura et al. 1998, Oda et al. 1998, Okajima et al. 1998, Erickson-Miller et al. 2000, and inferred from mouse homologs). STAT5A (MGH-STAT5) is phosphorylated on tyrosine-694 (Gouilleux et al. 1995, Arcasoy et al. 1999). Activation of STAT5 appears to be impaired in myelodysplastic syndrome (Hoefsloot et al. 1997). IGF-I enhances STAT5 phosphorylation in response to EPO (Okajima et al. 1998).
R-HSA-9012651 (Reactome) After being phosphorylated, phospho-STAT5 (STAT5A or STAT5B) dissociates from the EPO:EPOR complex, dimerizes, and transits to the nucleus where it activates transcription of target genes (Oda et al. 1998, and inferred from mouse homologs).
R-HSA-9012654 (Reactome) STAT5 (STAT5A or STAT5B) binds the phosphorylated cytoplasmic domain of EPOR via phosphotyrosine-343 and phosphotyrosine-479 of EPOR (Chretien et al. 1996, McGraw et al. 2012, and inferred from mouse homologs). STAT5 may also bind the EPOR complex indirectly via CRKL (Ota et al. 1998).
R-HSA-9012657 (Reactome) Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) binds phosphorylated IRS2 associated with the phosphorylated EPOR (Bouscary et al. 2003).
R-HSA-9021627 (Reactome) Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) associated with EPOR phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyl 3,4,5-trisphosphate (Kubota et al. 2001, Schmidt et al. 2004). PI3K binds the phosphorylated EPOR directly or indirectly via phosphorylated IRS2 or phosphorylated GAB1 (Bouscary et al. 2003).
R-HSA-9024723 (Reactome) CRKL, in a constitutive complex with RAPGEF1 (C3G, a nucleotide exchange factor for RAP1), binds the cytoplasmic domain of EPOR in the region of phosphotyrosine-460 (Arai et al. 2001).
R-HSA-9024726 (Reactome) LYN, in a complex with EPOR, phosphorylates CRKL bound to RAPGEF1 (Arai et al. 2001).
R-HSA-9027272 (Reactome) IRS2 is constitutively associated with EPOR and is phosphorylated on tyrosine residues in response to EPO (Verdier et al. 1997, Bouscary et al. 2003). The phosphorylated IRS2 serves as a docking site for downstream signaling proteins, notably phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) (Bouscary et al. 2003).
R-HSA-9027273 (Reactome) Phosphorylated JAK2 in a complex with EPOR and GAB1 phosphorylates GAB1 on unknown tyrosine residues (Lecoq-Lafon et al. 1999, Wickrema et al. 1999, Bouscary et al. 2003, Fukumoto et al. 2009). Phosphorylated GAB1 serves as a scaffold for binding downstream signaling molecules including phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) (Bouscary et al. 2003).
R-HSA-9027274 (Reactome) After stimulation by EPO, CRKL associates with EPOR, is phosphorylated, and binds SHC1 (inferred from mouse homologs).
R-HSA-9027275 (Reactome) Phosphorylated GAB1 in a complex with EPOR binds the p85 subunit of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) (Lecoq-Lafon et al. 1999, Wickrema et al. 1999, Bouscary et al. 2003).
R-HSA-9027280 (Reactome) Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) can directly bind phosphotyrosine-479 in the cytosolic domain of EPOR (Kubota et al. 2001, Bouscary et al. 2003, and inferred from mouse homologs).
R-HSA-9027281 (Reactome) GAB1 binds directly to phosphotyrosines 344 and 402 of the EPOR (Bouscary et al. 2003, Montoye et al. 2005). GAB1 can also indirectly bind the EPOR via SHC1 or GRB2. GAB2 is absent from human erythroid progenitors but present in mouse erythroid progenitors (Wickrema et al. 1999).
R-HSA-9027373 (Reactome) PLCG2 (PLCgamma2) binds phosphotyrosine-432 and phosphotyrosine-480 of EPOR (Montoye et al. 2005, and inferred from moue homologs). PLCG1 can also bind the phosphorylated EPOR (inferred from mouse homologs). After binding, PLCG2 is phosphorylated (Ren et al. 1994)
R-HSA-9027425 (Reactome) PLCG1 (Phospholipase C gamma1) or PLCG2 bound to the activated EPOR is phosphorylated on tyrosine residues by the kinase LYN (Ren et al. 1994, and inferred from mouse homologs).
R-HSA-9029149 (Reactome) Phosphorylated SHC1 in the EPOR complex serves as a scaffold to bind GRB2 bound to SOS1 (Damen et al. 1993, Odai et al. 1997). GRB2 may be pre-associated with VAV1 or SOS1, which are guanine nucleotide exchange factors for RAS, or with CBL, an ubiquitin ligase (Odai et al. 1997).
R-HSA-9029150 (Reactome) Phosphorylated SHC1 in a complex with the activated EPOR binds GRB2 bound to VAV1 (Hanazono et al. 1995, Hanazono et al. 1996, Odai et al. 1997). GRB2 exists in pre-assembled complexes with VAV1 (Hanazono et al. 1995), SOS1 (Odai et al. 1997), or CBL (Odai et al. 1997). VAV1 and SOS1 are guanine nucleotide exchange factors that activate the RAS signaling pathway.
R-HSA-9029151 (Reactome) Phosphorylated JAK2 phosphorylates VAV1 bound to GRB2 in a large complex assembled on the phosphorylated EPOR (Odai et al. 1997, Shigematsu et al. 1997). Phosphorylation of VAV1 activates its guanine nucleotide exchange activity (inferred from the mouse homolog).
R-HSA-9029155 (Reactome) Phosphorylated JAK2 associated with the EPOR complex phosphorylates SHC1 (Damen et al. 1993, Verma et al. 2014) bound to CRKL in the EPOR complex. The phosphorylated SHC1 serves as a scaffold to bind downstream effectors including GRB2:VAV1 and GRB2:SOS1.
R-HSA-9029158 (Reactome) SOS1 and phospho-VAV1 bound to GRB2 in a complex with the activated EPOR catalyze the exchange of GDP for GTP bound to RAS proteins, yielding RAS:GTP (Komatsu et al. 1992, Torti et al. 1992). RAS:GTP then activates RAF1 and ERK1 and ERK2. EPO is observed to activate HRAS (Komatsu et al. 1992, Torti et al. 1992), KRAS, and NRAS (inferred from mouse homologs). KRAS appears to be particularly important for erythropoiesis since deletion of KRAS causes anemia in mouse.
R-HSA-9032478 (Reactome) Phospholipase C gamma (PLCG1 or PLCG2) bound to the phosphorylated cytoplasmic domain of the EPO receptor (EPOR) hydrolyzes 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to yield the second messengers diacylglycerol and 1D-myo-inositol 1,4,5-trisphosphate (Ren et al. 1994, and inferred from mouse). Erythropoietin may also activate the hydrolysis of phosphatidylcholine and phosphatidylethanolamine (inferred from mouse homologs),
SHC1R-HSA-9027274 (Reactome)
STAT5A,STAT5BR-HSA-9012654 (Reactome)
p-STAT5A, p-STAT5BArrowR-HSA-9012651 (Reactome)
p21 RAS:GDPR-HSA-9029158 (Reactome)
p21 RAS:GTPArrowR-HSA-9029158 (Reactome)
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