Signaling by Erythropoietin (Homo sapiens)

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5, 7, 11, 14, 16...15, 27, 374, 4013, 43, 551, 20, 393, 366, 13, 353, 284813, 3520, 2512, 18, 27, 33, 34, 37...493, 19, 3028, 3213, 352, 4813, 43, 51, 5513, 29, 558, 10, 22, 23, 42...29, 4913, 231249cytosolextracellular regionp-STAT5A, p-STAT5BADPS-Farn-Me-2xPalmS HRAS ATPATPIRS2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:CRKL:RAPGEF1LYN EPO LYN S-Farn-Me KRAS4B p-Y-IRS2 IRS2 ATPLYN EPO EPO RAPGEF1 ATPp-12Y-JAK2 p-12Y-JAK2 STAT5B EPO EPO p-12Y-JAK2 IRS2 p-Y-IRS2 IRS2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-STAT5STAT5B RAPGEF1 IRS2 LYN p-12Y-JAK2 PIK3CG RAPGEF1 GDP ADPCRKL CRKL:RAPGEF1p-12Y-JAK2 p-12Y-JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2PI(3,4,5)P3DAGsPIK3CD EPO p-8Y-EPOR p-Y-SHC1 p-12Y-JAK2 IRS2 LYN EPO STAT5A EPO p-8Y-EPOR RAPGEF1 PIK3CG IRS2 ADPGRB2-1 S-Farn-Me-2xPalmS HRAS PIK3R5 GDPEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-PLCG1,2p-8Y-EPOR JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1,p-Y-VAV1LYN p-Y694-STAT5A p-Y-GAB1 ADPPIK3R5 PIK3CB S-Farn-Me KRAS4B S-Farn-Me PalmS NRAS EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2:PI3KEPO GAB1p-CRKL p-Y-PLCG2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PLCG1,2PIK3CA PI(4,5)P2GRB2-1 ADPEPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:GAB1EPO PLCG1 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:PI3KLYN p-12Y-JAK2 EPO PIK3R1 PIK3CD LYN PIK3R5 PIK3CB PI(4,5)P2IRS2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:SHC1EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:p-Y-IRS2EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1EPO ATPLYN p-12Y-JAK2 ATPCRKL LYN RAPGEF1 p-Y-VAV1 GRB2-1:VAV1PIK3CG GRB2-1 PIK3R1 p-12Y-JAK2 EPO EPO:EPOR:p-Y12-JAK2:LYN:IRS2LYN PIK3CD LYN IRS2 p-8Y-EPOR IRS2 PIK3CG PIK3R5 EPO p-CRKL LYN EPO LYN p-Y699-STAT5B PIK3CD EPOp-8Y-EPOR EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1SOS1 p-8Y-EPOR p-CRKL p21 RAS:GTPp-Y699-STAT5B IRS2 SHC1 p-8Y-EPOR p-CRKL IRS2 p-12Y-JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:STAT5GRB2-1 p-CRKL IRS2 LYN VAV1 p-8Y-EPOR p-8Y-EPOR LYN PIK3R1 p-Y-GAB1 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-Y-GAB1:PI3KSTAT5A H2Op-Y-GAB1 p-12Y-JAK2 EPO:EPOR:JAK2:LYN:IRS2SOS1 EPOR EPO p-12Y-JAK2 p-12Y-JAK2 SHC1S-Farn-Me PalmS NRAS IRS2 PI3K alpha, gammaPIK3CG EPO p-8Y-EPOR JAK2 p-12Y-JAK2 p-12Y-JAK2 PIK3R1 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:SOS1ADPADPp-8Y-EPOR p-8Y-EPOR IRS2 p-Y-IRS2 IRS2 p-8Y-EPOR p-12Y-JAK2 LYN S-Farn-Me-PalmS KRAS4A PIK3CA p-Y-SHC1 p-Y-SHC1 EPO PLC gamma1,2EPO GRB2-1 RAPGEF1 SOS1 p-8Y-EPOR I(1,4,5)P3GTPp-Y-VAV1 p-12Y-JAK2 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:p-Y-VAV1PIK3CB p-8Y-EPOR ATPS-Farn-Me-PalmS KRAS4A GAB1 IRS2 p-CRKL p-8Y-EPOR LYN p-Y-SHC1 ADPLYN p-8Y-EPOR GTP p-12Y-JAK2 RAPGEF1 ATPATPSTAT5A,STAT5Bp-12Y-JAK2 PIK3CB EPO PIK3CB p-8Y-EPOR IRS2 ADPp-Y-SHC1 LYN LYN GRB2-1 EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1p-CRKL PLCG2 p-Y694-STAT5A EPO:p-8Y-EPOR:p-12Y-JAK2:LYN:IRS2:p-CRKL:RAPGEF1:p-Y-SHC1:GRB2:VAV1RAPGEF1 PIK3R5 p-12Y-JAK2 PIK3CA EPOR p21 RAS:GDPIRS2 PI3K bound to EPORPIK3CA IRS2 LYN EPOR:JAK2:LYN:IRS2p-8Y-EPOR PLCG2 p-Y-PLCG1 PIK3CD EPO VAV1 LYN ATPADPPLCG1 PIK3R1 RAPGEF1 EPO p-8Y-EPOR PIK3CA EPOR GRB2-1:SOS1IRS2 4848139, 171346, 519, 179, 1731, 47, 54489, 1748139, 179, 17269, 173, 309, 179, 1748489, 179, 179, 17483, 19, 30266, 23, 359, 17139, 17139, 179, 173, 289, 179, 179, 179, 173, 30, 369, 17


Description

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.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9006335
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114943view16:46, 25 January 2021ReactomeTeamReactome version 75
113388view11:46, 2 November 2020ReactomeTeamReactome version 74
112593view15:56, 9 October 2020ReactomeTeamReactome version 73
101667view13:47, 1 November 2018DeSlOntology Term : 'erythropoietin signaling pathway' added !
101659view11:51, 1 November 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (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)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IRS2 ProteinQ9Y4H2 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
LYN ProteinP07948 (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)
S-Farn-Me KRAS4B ProteinP01116-2 (Uniprot-TrEMBL)
S-Farn-Me PalmS NRAS ProteinP01111 (Uniprot-TrEMBL)
S-Farn-Me-2xPalmS HRAS ProteinP01112 (Uniprot-TrEMBL)
S-Farn-Me-PalmS KRAS4A ProteinP01116-1 (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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