Interleukin-3, Interleukin-5 and GM-CSF signaling (Homo sapiens)

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7, 304, 4918, 2223, 532, 15, 388, 21, 27, 43503519, 313616, 34, 473732, 516, 1117, 33, 48264642, 5228, 41233, 20133, 292, 25131039, 43921240, 45, 52325, 14, 4491, 724, 463, 551IL3IL3R active complex, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RA IL3IL3R active complex, p-Y1007-JAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3RAIL3RBJAK2 IL5 homodimerIL5RApIL5 homodimer IL5 homodimer High affinity IL-5 receptor complex dimer, p-JAK2 PI3K delta PI3K delta IL3IL3RA GM-CSFGM-CSF receptor alpha subunitCommon beta chainJAK2 IL3IL3RA IL5 homodimerIL5RAppp85-containing Class 1A PI3Ks High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-IL5 homodimer IL3IL3RAIL3RBp-Y1007-JAK2 GM-CSFGM-CSF receptor alpha subunitpK63polyUb-PI3K alpha High affinity IL-5 receptor complex dimer, p-JAK2 IL5 homodimerIL5RACommon beta chainJAK2 PI3K beta High affinity IL-5 receptor complex dimer, inactive JAK2, pIL3IL3RAp-Y593,Y628-IL3RBJAK2 IL3IL3R active complex, phosphorylated BcpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pFYN-like kinasespGM-CSFGM-CSF receptor alpha subunitpInterleukin receptor compexes with activated ShcGRB2GAB2 IL3RAIL3pGM-CSFGM-CSF receptor alpha subunit IL5 homodimerIL5RA High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpPI3K beta High affinity IL-5 receptor complex dimer, inactive JAK2, pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pIL2RGJAK3 IL5 homodimer IL5 homodimer IL3IL3RA IL5 homodimerIL5RACommon beta chainp-JAK2 p85-containing Class 1A PI3Ks IL2IL2R trimer p-SHP2GRB2 IL3IL3R active complex, inactive JAK2, phosphorylated BcpIL2IL2R trimer p-GM-CSFGM-CSF receptor alpha subunit IL5 homodimerIL5RA IL2IL2R trimer p-High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL3IL3RA SHP-2/SHP-1 pY593,Y628-IL3RBJAK2 IL2IL2R trimer p-GM-CSFGM-CSF receptor alpha subunitCommon beta chainJAK2 GM-CSFGM-CSF receptor alpha subunit IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2 B-cell linker proteinpHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL3IL3R active complex, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RApHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimer pIL3IL3R active complex, inactive JAK2, phosphorylated BcSHC1 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3RA GRB2GAB2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-IL3IL3RA IL2IL2R trimer p-IL3IL3R active complex, p-Y1007-JAK2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, ppY593,Y628-IL3RBJAK2 pY593,Y628-IL3RBJAK2 pY593,Y628-IL3RBJAK2 Interleukin receptor complexes with activated SHC1 GM-CSFGM-CSF receptor alpha subunit IL3IL3R active complex, phosphorylated BcpHigh affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3RAp-Y593,Y628-IL3RBJAK2 IL3IL3RA IL5 homodimerIL5RApFYN-like kinasespIL3IL3R active complex, p-Y1007-JAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, pGM-CSFGM-CSF receptor alpha subunitpGM-CSFGM-CSF receptor alpha subunit GM-CSFGM-CSF receptor alpha subunit IL2IL2R trimer p-GM-CSFGM-CSF receptor alpha subunitpIL5 homodimerIL5RACommon beta chainJAK2 IL5 homodimerIL5RApIL2RGJAK3 GM-CSFGM-CSF receptor alpha subunitCommon beta chainJAK2 IL5 homodimerIL5RApHigh affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimer IL3IL3RA IL2IL2R trimer p-IL3IL3RAp-Y593,Y628-IL3RBJAK2 IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity GM-CSF receptor complex dimer, activated JAK2 IL3IL3RAIL3RBp-Y1007-JAK2 IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB Interleukin receptor complexes with activated SHC1SHIPGRB2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL5 homodimer IL5 homodimerIL5RA High affinity GM-CSF receptor complex dimer, inactive JAK2, pIL3RBJAK2 TECVAV1 IL3IL3RA High affinity IL-5 receptor complex dimer, inactive JAK2, pIL3IL3R active complex, phosphorylated BcpHigh affinity IL-5 receptor complex dimer, activated JAK2p-STAT5 pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3R active complex, phosphorylated Bc pIL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity GM-CSF receptor complex dimer, inactive JAK2, pIL3IL3R active complex, activated JAK2p-STAT5 GRB2SOS1 IL5 homodimerIL5RA High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2 GM-CSFGM-CSF receptor alpha subunit High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2p-STAT5 High affinity GM-CSF receptor complex dimer, activated JAK2 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,ppY593,Y628-IL3RBJAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated Bcpp-S585-IL3RBJAK2 IL5 homodimerIL5RACommon beta chainJAK2 IL3IL3R active complex, inactive JAK2, phosphorylated BcpGM-CSFGM-CSF receptor alpha subunit GM-CSFGM-CSF receptor alpha subunitpIL5 homodimer IL3IL3RAIL3RBJAK2 GM-CSFGM-CSF receptor alpha subunitpHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pIL2RGJAK3 High affinity IL-5 receptor complex dimer, p-JAK2 IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity IL-3 receptor complex dimer, inactive JAK2 IL3RBp-Y1007-JAK2 Interleukin receptor complexes with activated ShcGRB2p-GAB2p85-containing Class 1 PI3Ks GRB2GAB2 IL3IL3RAp-Y593,Y628-IL3RBJAK2 IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcSHC1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,pHigh affinity IL-5 receptor complex dimer, inactive JAK2, pIL3RBJAK2 High affinity binding complexes of interleukin receptors using the Common beta chain GM-CSFGM-CSF receptor alpha subunit PI3K beta IL5 homodimerIL5RACommon beta chainp-JAK2 GM-CSFGM-CSF receptor alpha subunitCommon beta chainp-JAK2 GM-CSFGM-CSF receptor alpha subunit IL2IL2R trimer pIL3IL3R active complex, phosphorylated BcpIL3IL3RAIL3RBp-Y1007-JAK2 IL3IL3RAp-Y593,Y628-IL3RBJAK2 GM-CSFGM-CSF receptor alpha subunitCommon beta chainp-JAK2 IL2IL2R trimer pIL5 homodimerIL5RACommon beta chainp-JAK2 IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB p85-containing Class 1A PI3Ks High affinity IL-5 receptor complex dimer, inactive JAK2, pPI3K alpha GM-CSFGM-CSF receptor alpha subunit PI3K alpha IL5 homodimer GM-CSFGM-CSF receptor alpha subunitCommon beta chainJAK2 IL3IL3RA IL5 homodimer IL2IL2R trimer p-Interleukin receptor complexes with activated SHC1 IL5 homodimerIL5RA IL5 homodimerIL5RA IL5 homodimerIL5RApSHIP1,2 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RApHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL3RBp-Y1007-JAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, pIL3IL3R active complex, activated JAK2, phosphorylated Bc IL3IL3RA IL3IL3R active complex, phosphorylated BcpPI3K delta IL5 homodimer High affinity IL-5 receptor complex dimer, activated JAK2STAT5 High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RApp-S585-IL3RBJAK2 IL5 homodimerIL5RApIL5 homodimerIL5RA IL5 homodimerIL5RA SHP-2/SHP-1 GM-CSFGM-CSF receptor alpha subunitCommon beta chainp-JAK2 High affinity IL-3 receptor complex dimer, inactive JAK2 IL3IL3RA High affinity GM-CSF receptor complex dimer, inactive JAK2, pIL3IL3RA IL3RBJAK2 IL5 homodimerIL5RApIL3IL3RAp-Y593,Y628-IL3RBJAK2 IL5 homodimer IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity IL-3 receptor complex dimer, inactive JAK2 IL3IL3R active complex, inactive JAK2, phosphorylated BcpIL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity GM-CSF receptor complex dimer, inactive JAK2, pIL5 homodimerIL5RA IL5 homodimerIL5RA IL3RAIL3pHigh affinity binding complex dimers of cytokine receptors using Bc. activated JAK2STAT5 HRASGDP pY593,Y628-IL3RBJAK2 IL2IL2R trimer p-HRASGTP High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, ppY593,Y628-IL3RBJAK2 PI3K alpha IL2IL2R trimer p-Interleukin receptor complexes with activated SHC1 Interleukin receptor complexes with activated SHC1SHIP1 p85-containing Class 1A PI3Ks GM-CSFGM-CSF receptor alpha subunit IL5 homodimerIL5RApHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pIL5 homodimer IL5 homodimerIL5RA IL5 homodimer IL3IL3RA High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RApHigh affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3RA High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RApp-S585-IL3RBJAK2 PI3K alpha IL3IL3RApS585-IL3RBJAK2 IL3IL3R active complex, p-Y1007-JAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpGM-CSFGM-CSF receptor alpha subunit IL5 homodimerIL5RA GM-CSFGM-CSF receptor alpha subunitpIL5 homodimer IL5 homodimerIL5RA IL2RGJAK3 PI3K beta IL2IL2R trimer p-IL3RBJAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, pPI3K delta IL2RGJAK3 IL3IL3R active complex, activated JAK2, phosphorylated Bc K63polyUb-PI3K delta Interleukin receptor complexes with activated SHC1GRB2SOS1 High affinity IL-5 receptor complex dimer, inactive JAK2, pIL5 homodimerIL5RA GM-CSFGM-CSF receptor alpha subunitpHigh affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3RA High affinity GM-CSF receptor complex dimer, inactive JAK2, pGM-CSFGM-CSF receptor alpha subunit ppY593,Y628-IL3RBJAK2 High affinity GM-CSF receptor complex dimer, inactive JAK2, pIL3IL3RA IL5 homodimerIL5RA IL3RBp-Y1007-JAK2 IL3IL3RAp-Y593,Y628-IL3RBJAK2 IL3IL3RA IL5 homodimer Interleukin receptor complexes with activated ShcGRB2p-GAB2 GM-CSFGM-CSF receptor alpha subunit IL5 homodimer High affinity IL-5 receptor complex dimer, inactive JAK2, pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pIL2IL2R trimer pCRK, CRKL pY593,Y628-IL3RBJAK2 IL5 homodimerIL5RApIL3IL3RApS585-IL3RBJAK2 IL5 homodimer High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL5 homodimerIL5RA IL2IL2R trimer p-pHigh affinity IL-5 receptor complex dimer, inactive JAK2, pGM-CSFGM-CSF receptor alpha subunitCommon beta chainp-JAK2 IL3IL3RA IL5 homodimerIL5RACommon beta chainp-JAK2 IL2IL2R trimer p-CRK, CRKL IL3IL3R active complex, phosphorylated Bc GM-CSFGM-CSF receptor alpha subunit IL3IL3R active complex, inactive JAK2, phosphorylated BcpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pHigh affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pnucleoplasmHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL3IL3RA High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpIL2IL2R trimer p-Interleukin receptor complexes with activated SHC1 GM-CSFGM-CSF receptor alpha subunitpIL3RBp-Y1007-JAK2 High affinity GM-CSF receptor complex dimer, inactive JAK2 High affinity IL-5 receptor complex dimer, inactive JAK2, pIL5 homodimerIL5RA Tyrosine kinases that phosphorylate the Common beta chain Interleukin receptor complexes with activated SHC1 pIL5 homodimer High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL2IL2R trimer p-IL3IL3RA IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB IL3IL3R active complex, activated JAK2, phosphorylated Bc IL3IL3RA p-STAT5A/B GM-CSFGM-CSF receptor alpha subunitppY593,Y628-IL3RBJAK2 IL5 homodimerIL5RACommon beta chainJAK2 STAT5 IL3RAIL3pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpIL3IL3RAp-Y593,Y628-IL3RBJAK2 IL3IL3RAp-Y593,Y628-IL3RBJAK2 IL2IL2R trimer pHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-IL3IL3R active complex, inactive JAK2, pIL3IL3RAp-Y593,Y628-IL3RBJAK2 GM-CSFGM-CSF receptor alpha subunit GM-CSFGM-CSF receptor alpha subunit IL5 homodimerIL5RApGM-CSFGM-CSF receptor alpha subunitpGM-CSFGM-CSF receptor alpha subunit High affinity IL-5 receptor complex dimer, inactive JAK2, pIL2RGJAK3 High affinity GM-CSF receptor complex dimer, activated JAK2 IL3IL3R active complex, activated JAK2STAT5 IL3IL3RA pY593,Y628-IL3RBJAK2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-IL3RBJAK2 IL3IL3R active complex, phosphorylated BcpGM-CSFGM-CSF receptor alpha subunitpGM-CSFGM-CSF receptor alpha subunit IL3RBJAK2 cytosolpIL3IL3RAp-Y593,Y628-IL3RBJAK2 Interleukin receptor complexes with activated SHC1SHIP1,2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pIL3IL3R active complex, phosphorylated BcpK63polyUb-PI3K beta GRB2pY-GAB2 GM-CSFGM-CSF receptor alpha subunitpIL5 homodimerIL5RA GM-CSFGM-CSF receptor alpha subunit IL5 homodimerIL5RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcSHC1 High affinity IL-5 receptor complex dimer, inactive JAK2 High affinity IL-3 receptor complex dimer, inactive JAK2 PI3K delta IL3IL3RAIL3RBJAK2 IL3IL3R active complex, phosphorylated Bc IL3IL3R active complex, JAK2p-Y593,Y629-IL3RB High affinity GM-CSF receptor complex dimer, inactive JAK2, pGRB2pY-GAB2 GRB2SOS1 IL3RBJAK2 IL5 homodimer IL5 homodimerIL5RA GM-CSFGM-CSF receptor alpha subunitpIL3IL3RAp-Y593,Y628-IL3RBJAK2 PI3K beta GM-CSFGM-CSF receptor alpha subunit IL2IL2R trimer p-IL5 homodimer IL3IL3RApS585-IL3RBJAK2 High affinity GM-CSF receptor complex dimer, activated JAK2p-STAT5 IL5 homodimerIL5RA IL5 homodimer IL5 homodimer IL2RGJAK3 GM-CSFGM-CSF receptor alpha subunit High affinity GM-CSF receptor complex dimer, inactive JAK2, pIL5 homodimer High affinity IL-5 receptor complex dimer, inactive JAK2, phosphorylated BcpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcpPI3K alpha High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-IL5 homodimerIL5RA GM-CSFGM-CSF receptor alpha subunit IL3IL3RAIL3RBJAK2 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-K63polyUb-p85-containing Class 1A PI3Ks High affinity GM-CSF receptor complex dimer, activated JAK2STAT5 IL3IL3RAIL3RBp-Y1007-JAK2 High affinity GM-CSF receptor complex dimer, inactive JAK2, phosphorylated BcppY593,Y628-IL3RBJAK2 IL2RGJAK3 Interleukin receptor complexes with activated SHC1SHIP1 IL3RAIL3pIL3IL3R active complex, JAK2p-Y593,Y629-IL3RB GM-CSFGM-CSF receptor alpha subunitpHigh affinity IL-5 receptor complex dimer, inactive JAK2, pFYN-like kinasesCBLGRB2p85-containing Class 1A PI3Ks IL5 homodimerIL5RA p85-containing Class 1A PI3Ks IL3IL3RA High affinity IL-5 receptor complex dimer, inactive JAK2, pGM-CSFGM-CSF receptor alpha subunitpHigh affinity GM-CSF receptor complex dimer, inactive JAK2, pCRKL IL5 SOS1 CSF2RB IL3 TECIL3RBJAK2JAK2 CRK, CRKLPIK3CB SHC1JAK2 IL5RA p-Y593,Y628-CSF2RB IL3 CSF2 p-Y1007-JAK2 IL3RA CSF2RA JAK2 GRB2-1 PIK3CD p-Y-SHC1 p-Y593,Y628-CSF2RB CSF2RB IL5RA CSF2RAHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pCSF2RA IL5 homodimerIL5RACommon beta chainJAK2SHC1 TECVAV1IL5 CSF2RA p85-containing Class 1A PI3KsIL5 Interleukin receptor complexes with activated ShcGRB2p-GAB2p85-containing Class 1 PI3KsRAPGEF1IL5 JAK2CSF2 IL5RA p-STAT5 dimerp-Y1007-JAK2 IL3 CSF2 IL5 homodimerpIL3RA IL3 IL5RA GRB2-1 Interleukin receptor compexes with activated ShcGRB2GAB2PIK3CB p-Y364,Y418,Y536-IL2RB PTPN11SHP-2/SHP-1CSF2 JAK2 p-S585-CSF2RB pCSF2RB IL2 GTP p-Y349,Y350,Y427-SHC1 p-Y700,Y731,Y774-CBL PIK3CD JAK3 GAB2 IL5RA IL3RA GRB2-1 GRB2-1 p-Y-JAK1 HRASGTPPRKACBIL5RA JAK2 IL2RA CRKIL3RA p-Y-SHC1 GM-CSFGM-CSF receptor alpha subunitCSF2 p-Y1007-JAK2 CSF2 IL2RG IL3 IL3 JAK2 CSF2ADPINPPL1 PIK3CD FYN-like kinasesADPCSF2RB p-Y1007-JAK2 IL3 FYN-like kinasespInterleukin receptor complexes with activated SHC1SHIP1,2p-Y694-STAT5A High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2STAT5CSF2RA p-Y700,Y731,Y774-CBL IL3 p-Y593,Y628-CSF2RB CSF2RA IL5 p-Y-SHC1 FYN-like kinasespJAK2 p-Y593,Y628-CSF2RB IL3RA p-Y-SHC1 Interleukin receptor complexes with activated SHC1GRB2SOS1GRB2-1PIK3CA IL5RA GRB2-1 JAK3 IL3IL3RAIL3RBJAK2p-Y593,Y628-CSF2RB IL3 IL3RA p-Y1007-JAK2 PIK3CB p-Y700,Y731,Y774-CBL High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pp-STAT5A/BIL5 PIK3CB JAK2 JAK2 p-Y1007-JAK2 STAT5A IL5 CBLIL3RA CSF2RB IL3RA p-Y-JAK1 p-Y-SHC1 IL2RG High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pPIK3CA Interleukin receptor complexes with activated ShcGRB2p-GAB2SHP2GRB2IL2RA CSF2RB GRB2-1 CSF2 IL2RA GTPCSF2RA IL5RA HRASHigh affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,pPIK3CA GRB2-1 IL3RA Interleukin receptor complexes with activated SHC1SHIP1JAK3 IL5RA RAPGEF1 IL3RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-JAK2 p-Y349,Y350,Y427-SHC1 JAK2 JAK2 IL3RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2CSF2RB p-Y-JAK1 IL3 GRB2-1 CSF2RA p-Y-SHC1 p-Y593,Y628-CSF2RB SHIP1,2CSF2 IL5 IL5RA High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2p-STAT5PIK3CA CSF2RA CSF2 PTPN6 CSF2RA CSF2RA CSF2 TEC p-Y364,Y418,Y536-IL2RB p-Y699-STAT5B CSF2RA JAK3 IL5RA IL5 CSF2RA IL2RA IL5 JAK2 p-Y-JAK1 p-Y593,Y628-CSF2RB JAK3 p-Y-JAK1 p-Y349,Y350,Y427-SHC1 IL5 p-Y364,Y418,Y536-IL2RB K48polyUbIL2 JAK2 CSF2RA IL3RA ATPp-Y593,Y628-CSF2RB IL3RA ATPp-Y-JAK1 IL5RA JAK2 IL3 CSF2 IL3 p-Y-GAB2 CSF2RA CSF2RB p-Y-SHC1 JAK2 p-Y364,Y418,Y536-IL2RB p-Y349,Y350,Y427-SHC1 PTPN6 p-S585-CSF2RB ADPPIK3CB IL5RA IL3 IL2 VAV1 IL3RA IL2RG IL2RA PTPN6 IL5RA HRASGDPp-Y593-CSF2RB CSF2RA IL5RA B-cell linker proteinpGDPInterleukin receptor complexes with activated SHC1SHIPGRB2STAT5B IL3 IL5 p-Y349,Y350,Y427-SHC1 VAV1PTPN6 IL2RA p-Y349,Y350,Y427-SHC1 IL5 IL5JAK2 IL2RA IL2 Interleukin receptor complexes with activated SHC1IL3 IL2 High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2p-Y593,Y628-CSF2RB IL5 IL2RG IL2RG p-Y1007-JAK2 p-Y700,Y731,Y774-CBL JAK2 CSF2 IL5RA BLNKp-STAT5 dimerIL5RA CSF2 p-Y349,Y350,Y427-SHC1 IL3RA High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pGRB2GAB2High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,pIL3 CSF2 IL5 IL5 IL5RAIL3RA CSF2 IL3 GAB2 GRB2-1 IL3 IL5RA p-Y-GAB2 ATPCSF2 GDP JAK3 HRASIL3RA p-Y700,Y731,Y774-CBL IL5 IL3RA p-Y-SHC1 PIK3CA STAT5PIK3CB CSF2RA CSF2 GRB2SOS1JAK3 IL2RG IL3RA IL3RA CSF2RA IL5 IL5 p-Y364,Y418,Y536-IL2RB CBL SOS1 IL5 p-Y593,Y628-CSF2RB IL3 pIL2 ADPCSF2RB p-Y364,Y418,Y536-IL2RB CRKL JAK2 CSF2 p-Y349,Y350,Y427-SHC1 Tyrosine kinases that phosphorylate the Common beta chainIL2 VAV1 p-Y700,Y731,Y774-CBLIL5RA p-Y593,Y628-CSF2RB p-Y349,Y350,Y427-SHC1 ADPYWHAZ PTPN11 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pCRKCSF2RA FYN-like kinasesCBLGRB2p85-containing Class 1A PI3KsCSF2 p-Y-JAK1 IL5 GRB2-1 IL5RA CSF2RA GM-CSFGM-CSF receptor alpha subunitCommon beta chainJAK2IL3p-S585-CSF2RB CSF2RBIL3 IL2 IL3 JAK3 CSF2 IL5RA IL2RG IL5 IL3RA CSF2RA IL2RA IL3RA ATPIL3IL3RAIL3 JAK2 YWHAZIL5 IL5 homodimerIL5RACSF2RA GRB2-1 JAK2 IL5RA ATPPTPN11 CSF2 PIK3CD CSF2RA YWHAZ IL5 p-Y364,Y418,Y536-IL2RB JAK2 CSF2RA IL3 PIK3CD PIK3CA IL5RA p-Y364,Y418,Y536-IL2RB p-Y-JAK1 CSF2 IL3 IL3RAIL3RA p-Y700,Y731,Y774-CBL IL3RA IL5RA PTPN11 JAK2 BLNK CSF2RA CSF2 IL2RG p-Y593,Y628-CSF2RB PIK3CD High affinity binding complexes of interleukin receptors using the Common beta chainINPP5D IL5 CSF2RB CSF2


Description

The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.

IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).

All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).

The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).



Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=512988

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Bibliography

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  1. Marengère LE, Mirtsos C, Kozieradzki I, Veillette A, Mak TW, Penninger JM.; ''Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells.''; PubMed Europe PMC Scholia
  2. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  3. Sakamaki K, Miyajima I, Kitamura T, Miyajima A.; ''Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  4. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T.; ''Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.''; PubMed Europe PMC Scholia
  5. Guthridge MA, Stomski FC, Thomas D, Woodcock JM, Bagley CJ, Berndt MC, Lopez AF.; ''Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors.''; PubMed Europe PMC Scholia
  6. Stomski FC, Dottore M, Winnall W, Guthridge MA, Woodcock J, Bagley CJ, Thomas DT, Andrews RK, Berndt MC, Lopez AF.; ''Identification of a 14-3-3 binding sequence in the common beta chain of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors that is serine-phosphorylated by GM-CSF.''; PubMed Europe PMC Scholia
  7. 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 Scholia
  8. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  9. Stomski FC, Woodcock JM, Zacharakis B, Bagley CJ, Sun Q, Lopez AF.; ''Identification of a Cys motif in the common beta chain of the interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 receptors essential for disulfide-linked receptor heterodimerization and activation of all three receptors.''; PubMed Europe PMC Scholia
  10. Milburn MV, Hassell AM, Lambert MH, Jordan SR, Proudfoot AE, Graber P, Wells TN.; ''A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5.''; PubMed Europe PMC Scholia
  11. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  12. Gu H, Pratt JC, Burakoff SJ, Neel BG.; ''Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation.''; PubMed Europe PMC Scholia
  13. Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC.; ''Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.''; PubMed Europe PMC Scholia
  14. Harkiolaki M, Tsirka T, Lewitzky M, Simister PC, Joshi D, Bird LE, Jones EY, O'Reilly N, Feller SM.; ''Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2.''; PubMed Europe PMC Scholia
  15. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  16. Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC.; ''Engagement of Gab1 and Gab2 in erythropoietin signaling.''; PubMed Europe PMC Scholia
  17. Hunter S, Koch BL, Anderson SM.; ''Phosphorylation of cbl after stimulation of Nb2 cells with prolactin and its association with phosphatidylinositol 3-kinase.''; PubMed Europe PMC Scholia
  18. Odai H, Sasaki K, Iwamatsu A, Nakamoto T, Ueno H, Yamagata T, Mitani K, Yazaki Y, Hirai H.; ''Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl.''; PubMed Europe PMC Scholia
  19. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  20. Devos R, Plaetinck G, Van der Heyden J, Cornelis S, Vandekerckhove J, Fiers W, Tavernier J.; ''Molecular basis of a high affinity murine interleukin-5 receptor.''; PubMed Europe PMC Scholia
  21. Rosenthal LA, Winestock KD, Finbloom DS.; ''IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts.''; PubMed Europe PMC Scholia
  22. Salcini AE, McGlade J, Pelicci G, Nicoletti I, Pawson T, Pelicci PG.; ''Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins.''; PubMed Europe PMC Scholia
  23. Reedquist KA, Fukazawa T, Panchamoorthy G, Langdon WY, Shoelson SE, Druker BJ, Band H.; ''Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G.''; PubMed Europe PMC Scholia
  24. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  25. Duronio V, Clark-Lewis I, Federsppiel B, Wieler JS, Schrader JW.; ''Tyrosine phosphorylation of receptor beta subunits and common substrates in response to interleukin-3 and granulocyte-macrophage colony-stimulating factor.''; PubMed Europe PMC Scholia
  26. Feshchenko EA, Langdon WY, Tsygankov AY.; ''Fyn, Yes, and Syk phosphorylation sites in c-Cbl map to the same tyrosine residues that become phosphorylated in activated T cells.''; PubMed Europe PMC Scholia
  27. Gotoh N, Tojo A, Shibuya M.; ''A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL-3.''; PubMed Europe PMC Scholia
  28. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  29. Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA, Franklin RA, Oberhaus SM, Steelman LS, McCubrey JA.; ''Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs.''; PubMed Europe PMC Scholia
  30. Brockdorff JL, Gu H, Mustelin T, Kaltoft K, Geisler C, Röpke C, Ødum N.; ''Gab2 is phosphorylated on tyrosine upon interleukin-2/interleukin-15 stimulation in mycosis-fungoides-derived tumor T cells and associates inducibly with SHP-2 and Stat5a.''; PubMed Europe PMC Scholia
  31. Anderson SM, Burton EA, Koch BL.; ''Phosphorylation of Cbl following stimulation with interleukin-3 and its association with Grb2, Fyn, and phosphatidylinositol 3-kinase.''; PubMed Europe PMC Scholia
  32. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  33. Odai H, Sasaki K, Iwamatsu A, Hanazono Y, Tanaka T, Mitani K, Yazaki Y, Hirai H.; ''The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells.''; PubMed Europe PMC Scholia
  34. 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 Scholia
  35. Miura-Shimura Y, Duan L, Rao NL, Reddi AL, Shimura H, Rottapel R, Druker BJ, Tsygankov A, Band V, Band H.; ''Cbl-mediated ubiquitinylation and negative regulation of Vav.''; PubMed Europe PMC Scholia
  36. Hayashida K, Kitamura T, Gorman DM, Arai K, Yokota T, Miyajima A.; ''Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor.''; PubMed Europe PMC Scholia
  37. Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ.; ''FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival.''; PubMed Europe PMC Scholia
  38. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMed Europe PMC Scholia
  39. Dorsch M, Hock H, Diamantstein T.; ''Tyrosine phosphorylation of Shc is induced by IL-3, IL-5 and GM-CSF.''; PubMed Europe PMC Scholia
  40. Pratt JC, Weiss M, Sieff CA, Shoelson SE, Burakoff SJ, Ravichandran KS.; ''Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor.''; PubMed Europe PMC Scholia
  41. Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMed Europe PMC Scholia
  42. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G.; ''A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF.''; PubMed Europe PMC Scholia
  43. Harmer SL, DeFranco AL.; ''The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes.''; PubMed Europe PMC Scholia
  44. Bone H, Dechert U, Jirik F, Schrader JW, Welham MJ.; ''SHP1 and SHP2 protein-tyrosine phosphatases associate with betac after interleukin-3-induced receptor tyrosine phosphorylation. Identification of potential binding sites and substrates.''; PubMed Europe PMC Scholia
  45. Lamkin TD, Walk SF, Liu L, Damen JE, Krystal G, Ravichandran KS.; ''Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in vivo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP.''; PubMed Europe PMC Scholia
  46. 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 Scholia
  47. Kline JB, Moore DJ, Clevenger CV.; ''Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site.''; PubMed Europe PMC Scholia
  48. Orban PC, Levings MK, Schrader JW.; ''Heterodimerization of the alpha and beta chains of the interleukin-3 (IL-3) receptor is necessary and sufficient for IL-3-induced mitogenesis.''; PubMed Europe PMC Scholia
  49. Guthridge MA, Stomski FC, Barry EF, Winnall W, Woodcock JM, McClure BJ, Dottore M, Berndt MC, Lopez AF.; ''Site-specific serine phosphorylation of the IL-3 receptor is required for hemopoietic cell survival.''; PubMed Europe PMC Scholia
  50. Flores-Morales A, Pircher TJ, Silvennoinen O, Gustafsson JA, Sanchez-Gomez M, Norstedt G, Haldosén LA, Wood TJ.; ''In vitro interaction between STAT 5 and JAK 2; dependence upon phosphorylation status of STAT 5 and JAK 2.''; PubMed Europe PMC Scholia
  51. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW.; ''The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation.''; PubMed Europe PMC Scholia
  52. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  53. Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A, Griffin JD, Ihle JN.; ''JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region.''; PubMed Europe PMC Scholia
  54. Song H, Zhang J, Chiang YJ, Siraganian RP, Hodes RJ.; ''Redundancy in B cell developmental pathways: c-Cbl inactivation rescues early B cell development through a B cell linker protein-independent pathway.''; PubMed Europe PMC Scholia
  55. Kitamura T, Sato N, Arai K, Miyajima A.; ''Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors.''; PubMed Europe PMC Scholia
  56. Gearing DP, King JA, Gough NM, Nicola NA.; ''Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor.''; PubMed Europe PMC Scholia
  57. Park RK, Kyono WT, Liu Y, Durden DL.; ''CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling.''; PubMed Europe PMC Scholia
  58. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  59. Sorensen P, Mui AL, Krystal G.; ''Interleukin-3 stimulates the tyrosine phosphorylation of the 140-kilodalton interleukin-3 receptor.''; PubMed Europe PMC Scholia
  60. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  61. Stanton ML, Brodeur PH.; ''Stat5 mediates the IL-7-induced accessibility of a representative D-Distal VH gene.''; PubMed Europe PMC Scholia
  62. Andoniou CE, Thien CB, Langdon WY.; ''The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain.''; PubMed Europe PMC Scholia
  63. Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH, Neel BG.; ''New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway.''; PubMed Europe PMC Scholia
  64. Fang D, Liu YC.; ''Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells.''; PubMed Europe PMC Scholia
  65. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  66. Feng J, Witthuhn BA, Matsuda T, Kohlhuber F, Kerr IM, Ihle JN.; ''Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.''; PubMed Europe PMC Scholia
  67. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  68. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  69. Ravichandran KS, Burakoff SJ.; ''The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation.''; PubMed Europe PMC Scholia
  70. Ingham RJ, Okada H, Dang-Lawson M, Dinglasan J, van Der Geer P, Kurosaki T, Gold MR.; ''Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase.''; PubMed Europe PMC Scholia
  71. Machide M, Mano H, Todokoro K.; ''Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain.''; PubMed Europe PMC Scholia

History

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114742view16:22, 25 January 2021ReactomeTeamReactome version 75
113186view11:25, 2 November 2020ReactomeTeamReactome version 74
112414view15:35, 9 October 2020ReactomeTeamReactome version 73
101318view11:20, 1 November 2018ReactomeTeamreactome version 66
100855view20:52, 31 October 2018ReactomeTeamreactome version 65
100396view19:26, 31 October 2018ReactomeTeamreactome version 64
99944view16:11, 31 October 2018ReactomeTeamreactome version 63
99500view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99148view12:41, 31 October 2018ReactomeTeamreactome version 62
93872view13:42, 16 August 2017ReactomeTeamreactome version 61
93439view11:23, 9 August 2017ReactomeTeamreactome version 61
86530view09:20, 11 July 2016ReactomeTeamreactome version 56
83413view11:10, 18 November 2015ReactomeTeamVersion54
81612view13:09, 21 August 2015ReactomeTeamVersion53
77073view08:37, 17 July 2014ReactomeTeamFixed remaining interactions
76778view12:14, 16 July 2014ReactomeTeamFixed remaining interactions
76100view10:16, 11 June 2014ReactomeTeamRe-fixing comment source
75812view11:35, 10 June 2014ReactomeTeamReactome 48 Update
75162view14:11, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74809view08:54, 30 April 2014ReactomeTeamReactome46
44874view10:01, 6 October 2011MartijnVanIerselOntology Term : 'Interleukin mediated signaling pathway' added !
42059view21:53, 4 March 2011MaintBotAutomatic update
39866view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
B-cell linker protein pComplexREACT_24555 (Reactome)
BLNK ProteinQ8WV28 (Uniprot-TrEMBL)
BLNKProteinQ8WV28 (Uniprot-TrEMBL)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CRK, CRKLProteinREACT_24469 (Reactome)
CRKL ProteinP46109 (Uniprot-TrEMBL)
CRKProteinP46108 (Uniprot-TrEMBL)
CSF2 ProteinP04141 (Uniprot-TrEMBL)
CSF2ProteinP04141 (Uniprot-TrEMBL)
CSF2RA ProteinP15509 (Uniprot-TrEMBL)
CSF2RAProteinP15509 (Uniprot-TrEMBL)
CSF2RB ProteinP32927 (Uniprot-TrEMBL)
CSF2RBProteinP32927 (Uniprot-TrEMBL)
FYN-like kinases

CBL GRB2

p85-containing Class 1A PI3Ks		ComplexREACT_24661 (Reactome)
FYN-like kinases pComplexREACT_24228 (Reactome)
FYN-like kinases pComplexREACT_24386 (Reactome)
FYN-like kinasesProteinREACT_24391 (Reactome)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GM-CSF

GM-CSF receptor alpha subunit Common beta chain

JAK2		ComplexREACT_24858 (Reactome)
GM-CSF GM-CSF receptor alpha subunitComplexREACT_24102 (Reactome)
GRB2 GAB2ComplexREACT_24714 (Reactome)
GRB2 SOS1ComplexREACT_4435 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HRAS GDPComplexREACT_24031 (Reactome)
HRAS GTPComplexREACT_24217 (Reactome)
HRASProteinP01112 (Uniprot-TrEMBL)
High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2 p-STAT5ComplexREACT_24628 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2ComplexREACT_24626 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p-ComplexREACT_24225 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pComplexREACT_24147 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pComplexREACT_24222 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pComplexREACT_24243 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pComplexREACT_24266 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pComplexREACT_24884 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,pComplexREACT_24560 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,pComplexREACT_24887 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2ComplexREACT_24738 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2 STAT5ComplexREACT_24047 (Reactome)
High affinity binding complexes of interleukin receptors using the Common beta chainComplexREACT_24474 (Reactome)
IL2 ProteinP60568 (Uniprot-TrEMBL)
IL2RA ProteinP01589 (Uniprot-TrEMBL)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
IL3

IL3RA IL3RB

JAK2		ComplexREACT_24229 (Reactome)
IL3 IL3RAComplexREACT_24866 (Reactome)
IL3 ProteinP08700 (Uniprot-TrEMBL)
IL3ProteinP08700 (Uniprot-TrEMBL)
IL3RA ProteinP26951 (Uniprot-TrEMBL)
IL3RAProteinP26951 (Uniprot-TrEMBL)
IL3RB JAK2ComplexREACT_24165 (Reactome)
IL5 ProteinP05113 (Uniprot-TrEMBL)
IL5 homodimer

IL5RA Common beta chain

JAK2		ComplexREACT_24214 (Reactome)
IL5 homodimer IL5RAComplexREACT_24270 (Reactome)
IL5 homodimerComplexREACT_24473 (Reactome)
IL5ProteinP05113 (Uniprot-TrEMBL)
IL5RA ProteinQ01344 (Uniprot-TrEMBL)
IL5RAProteinQ01344 (Uniprot-TrEMBL)
INPP5D ProteinQ92835 (Uniprot-TrEMBL)
INPPL1 ProteinO15357 (Uniprot-TrEMBL)
Interleukin receptor compexes with activated Shc

GRB2

GAB2		ComplexREACT_24494 (Reactome)
Interleukin receptor complexes with activated SHC1

GRB2

SOS1		ComplexREACT_24582 (Reactome)
Interleukin receptor complexes with activated SHC1

SHIP

GRB2		ComplexREACT_24297 (Reactome)
Interleukin receptor complexes with activated SHC1 SHIP1,2ComplexREACT_24093 (Reactome)
Interleukin receptor complexes with activated SHC1 SHIP1ComplexREACT_24554 (Reactome)
Interleukin receptor complexes with activated SHC1ComplexREACT_24730 (Reactome)
Interleukin receptor complexes with activated Shc

GRB2 p-GAB2

p85-containing Class 1 PI3Ks		ComplexREACT_24797 (Reactome)
Interleukin receptor complexes with activated Shc

GRB2

p-GAB2		ComplexREACT_24779 (Reactome)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2ProteinO60674 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
K48polyUbREACT_24769 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PRKACBProteinP22694 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
RAPGEF1 ProteinQ13905 (Uniprot-TrEMBL)
RAPGEF1ProteinQ13905 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SHIP1,2ProteinREACT_24095 (Reactome)
SHP-2/SHP-1ProteinREACT_20250 (Reactome)
SHP2 GRB2ComplexREACT_24568 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
STAT5ProteinREACT_24211 (Reactome)
TEC VAV1ComplexREACT_24039 (Reactome)
TEC ProteinP42680 (Uniprot-TrEMBL)
TECProteinP42680 (Uniprot-TrEMBL)
Tyrosine kinases that phosphorylate the Common beta chainComplexREACT_24291 (Reactome)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1ProteinP15498 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
YWHAZProteinP63104 (Uniprot-TrEMBL)
p-S585-CSF2RB ProteinP32927 (Uniprot-TrEMBL)
p-STAT5 dimerREACT_24109 (Reactome)
p-STAT5 dimerREACT_24289 (Reactome)
p-STAT5A/BREACT_24299 (Reactome)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y349,Y350,Y427-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y364,Y418,Y536-IL2RB ProteinP14784 (Uniprot-TrEMBL)
p-Y593,Y628-CSF2RB ProteinP32927 (Uniprot-TrEMBL)
p-Y593-CSF2RB ProteinP32927 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y700,Y731,Y774-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y700,Y731,Y774-CBLProteinP22681 (Uniprot-TrEMBL)
p85-containing Class 1A PI3KsComplexREACT_24162 (Reactome) This set represents Class 1A PI3Ks including all three genes that can give rise to the five isoforms of the regulatory subunit. Note that the p85 alpha form is almost always the form used experimentally (especially where p85-Abs are used) - the other forms are rarely shown experimentally. Also note it may not be the most relevant physiologically in some cell types (e.g. T cells).
pComplexREACT_24589 (Reactome)
pComplexREACT_24612 (Reactome)
pComplexREACT_24764 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowREACT_23782 (Reactome)
ADPArrowREACT_23842 (Reactome)
ADPArrowREACT_23845 (Reactome)
ADPArrowREACT_23935 (Reactome)
ADPArrowREACT_23953 (Reactome)
ATPREACT_23782 (Reactome)
ATPREACT_23842 (Reactome)
ATPREACT_23845 (Reactome)
ATPREACT_23935 (Reactome)
ATPREACT_23953 (Reactome)
BLNKREACT_23998 (Reactome)
CBLREACT_23799 (Reactome)
CRK, CRKLREACT_23925 (Reactome)
CSF2RAREACT_23919 (Reactome)
CSF2RBREACT_23962 (Reactome)
CSF2REACT_23919 (Reactome)
FYN-like kinases

CBL GRB2

p85-containing Class 1A PI3Ks		REACT_23845 (Reactome)
FYN-like kinases pArrowREACT_23845 (Reactome)
FYN-like kinases pREACT_23869 (Reactome)
FYN-like kinasesREACT_23799 (Reactome)
GDPArrowREACT_23928 (Reactome)
GM-CSF GM-CSF receptor alpha subunitREACT_23875 (Reactome)
GRB2 GAB2REACT_23856 (Reactome)
GRB2 SOS1REACT_23828 (Reactome)
GRB2-1REACT_23799 (Reactome)
GRB2-1REACT_23911 (Reactome)
GRB2-1REACT_23965 (Reactome)
GTPREACT_23928 (Reactome)
HRAS GDPREACT_23928 (Reactome)
HRAS GTPArrowREACT_23928 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2 p-STAT5ArrowREACT_23842 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2ArrowREACT_23896 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2ArrowREACT_23935 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, activated JAK2REACT_23884 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pArrowREACT_23953 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pREACT_23857 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pREACT_23861 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pREACT_23870 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, pREACT_24014 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2,pREACT_23816 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2REACT_23935 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2REACT_23953 (Reactome)
High affinity binding complex dimers of cytokine receptors using Bc. activated JAK2 STAT5REACT_23842 (Reactome)
IL3 IL3RAREACT_23772 (Reactome)
IL3RAREACT_23939 (Reactome)
IL3RB JAK2REACT_23772 (Reactome)
IL3RB JAK2REACT_23875 (Reactome)
IL3RB JAK2REACT_23992 (Reactome)
IL3REACT_23939 (Reactome)
IL5 homodimer IL5RAREACT_23992 (Reactome)
IL5 homodimerREACT_23969 (Reactome)
IL5RAREACT_23969 (Reactome)
Interleukin receptor compexes with activated Shc

GRB2

GAB2		REACT_23782 (Reactome)
Interleukin receptor complexes with activated SHC1

GRB2

SOS1		REACT_23928 (Reactome)
Interleukin receptor complexes with activated SHC1 SHIP1REACT_23911 (Reactome)
Interleukin receptor complexes with activated SHC1REACT_23828 (Reactome)
Interleukin receptor complexes with activated SHC1REACT_23856 (Reactome)
Interleukin receptor complexes with activated SHC1REACT_23874 (Reactome)
Interleukin receptor complexes with activated Shc

GRB2

p-GAB2		ArrowREACT_23782 (Reactome)
Interleukin receptor complexes with activated Shc

GRB2

p-GAB2		REACT_24024 (Reactome)
JAK2REACT_23962 (Reactome)
K48polyUbREACT_23869 (Reactome)
PRKACBREACT_23999 (Reactome)
PTPN11REACT_23965 (Reactome)
RAPGEF1REACT_23785 (Reactome)
REACT_23772 (Reactome) The alpha subunit of the IL3 receptor binds IL 3 with low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of ligand with the alpha chain to form a binary complex. This binary complex is then able to bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008). Covalent linkage of the receptor subunits is required for receptor signalling (Stomski et al. 1996).
REACT_23774 (Reactome) STAT5A and STAT5B dimers bind to similar core gamma-interferon activated sequence (GAS) motifs (Soldaini et al., 2000). STAT5a/b also form homo- and hetero-tetramers with distinct or expanded DNA-binding properties. Genes that are regulated by STAT5 include IL2RA (John et al. 1996), TNFSF11 (RANKL), Connexin-26 (GJB2) and Cyclin D1 (Hennighausen & Robinson, 2005). A comprehensive listing of hepatic STAT5b regulated genes is available from microarray/STAT5b knockout mice (Clodfelter et al. 2006), and similarly for STAT5-dependent genes regulated by the GH receptor (Rowland et al. 2005, Barclay et al. 2011).
REACT_23782 (Reactome) Binding of Gab2 to tyrosine phosphorylated Shc promotes the phosphorylation of Gab2 by an unknown kinase. Gab2 becomes tyrosine phosphorylated in response to IL-2 (Brockdorff et al. 2001) and IL-3 (Gu et al. 1998). Chimeric receptors were used to demonstrate that Shc is sufficient for Gab2 tyrosine phosphorylation. In response to IL-3, Grb2 was also required, reflecting that Gab2 is recruited to the activated cytokine receptor complex as a complex of Gab2:Grb2 (Gu et al. 2000).
REACT_23785 (Reactome) Cbl has been identified in ternary complexes with CRKL and C3G (RAPGEF1)(Reedquist et al. 1996) a Rap1 GEF, suggesting a role for Cbl in linking cytokine stimulation to Rap1 activation. Consistent with this, stimulation of NB-4 promyelocytic cells by IFN-gamma causes tyrosine phosphorylation and association of Cbl with CRKL followed by activation of Rap1 (Alsayed et al. 2000) and tyrosine phosphorylation of Cbl and its association with CRKL correlated with an increase in Rap 1 activity in anergic T cells (Boussiotis et al. 1997).
REACT_23799 (Reactome) Cbl is constitutively associated with Grb2 in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain can bind the adaptor protein CRKL.

Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998).
Cbl also associates with Fyn (Anderson et al. 1997) and the related kinases Hck and Lyn (Hunter et al. 1999). Binding studies indicate that this binding is independent of the phosphorylation state of Cbl; The association of Fyn with Cbl has been described as constitutive (Hunter et al. 1999).

Cbl further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this is also described as constitutive and is mediated by the SH3 domain of p85 (Hunter et al. 1997).
REACT_23816 (Reactome) Synthetic phosphopeptides based on Bc were dephosphorylated by SHP1 and SHP2, peptides phosphorylated at Y628 were the best substrate followed by those phosphorylated at Y766.
REACT_23827 (Reactome) The STAT5a and STAT5b forms are encoded by 2 closely-related genes. They are thought to be present largely as monomers in unstimulated cells but rapidly form homo- and hetero-dimers upon stimulation (Cella et al. 1998). Tyrosine phosphorylation of STAT monomers allows dimers to form through reciprocal phosphotyrosine-SH2 interactions. The dimers translocate to the nucleus and bind to STAT-specific DNA-response elements of target genes to induce gene transcription (Baker et al.2007). STAT5a/b homo- and hetero-tetramers have also been shown to occur downstream of IL-2 and may have a distinct or expanded target repertoire from STAT5a/b dimers. Although STAT5a and STAT5b are highly homologous at the DNA and protein levels, each has unique funcions, as demonstrated by studies comparing mice lacking one isoform or the other. However, it is also known that STAT5a and STAT5b share a number of functions and that the phenotype of mice lacking both STAT5a and STAT5b is more severe than those lacking either one individually, which suggest that there may be some redundancy or that they cooperate in order to achieve the full spectrum of STAT5-dependent activities (Moriggl et al. 1999, Teglund et al. 1998).
REACT_23828 (Reactome) Shc is tyrosine phosphorylated by an unidentified kinase, creating a docking site for the SH2 domain of Grb2 (Zhu et al. 1994). Grb2 is an adaptor protein believed to be constitutively associated with the guanine nucleotide exchange protein Sos1 (often abbreviated to Sos). Recruitment of the Grb2:Sos1 complex leads to activation of the Ras pathway (Ravichandran & Burakoff 1994) and consequently activation of the MAPK pathway.
REACT_23842 (Reactome) JAK2 phosphorylates STAT5; phosphorylated STAT5 dimerizes and translocates to the nucleus (Darnell et al., 1994), binds DNA and activates target genes including c-fos, pim-1, oncostatin M, and Id-1 (Mui et al. 1996). STAT5 activation is believed to be the primary signaling mechanism for Bc (Ihle, 2001).
REACT_23845 (Reactome) Cbl is tyrosine phosphorylated following stimulation with IL-3 (Anderson et al. 1997) and GM-CSF (Odai et al. 1995). Cbl may be phosphorylated prior to this IL-3 stimulated tyrosyl phosphorylation (Park et al. 1998). The kinase responsible for Cbl phosphorylation may be dependent on cell type; Fyn is demonstrated to have the ability to phosphorylate Cbl (Hunter et al. 1999), other candidates include Hck, Lyn (Hunter et al. 1999) and Syk (Park et al. 1998).

Tyrosines 700, 731 and 774 are the major sites of Cbl phosphorylation by non-receptor protein tyrosine kinases, with none showing any particular specificity for sites (Tsygankov et al. 2001). Fyn was observed to be constitutively associated with Cbl in lysates of several different cell types including the interleukin-3-dependent murine myeloid cell line 32Dcl3, and the prolactin-dependent rat thymoma cell line Nb2. Cbl phosphorylation at Y731 is postulated to provide an additional interaction between Cbl and the SH2 domain of p85-PI3K (Hunter et al. 1999). Cbl-p85 association increases in activated cells (Panchamoorthy et al. 1996). Expression of a Cbl Y731F mutant which abolishes binding of Cbl to p85 markedly increased levels of p85-PI3K (Dufour et al. 2008). Cbl-p85 binding negatively regulates PI3K activity (Fang et al. 2001); Cbl phosphorylation increased PI3K ubiquitination and proteasome degradation (Dufour et al. 2008). Cbl association with members of the Crk family is mediated by phosphorylation of Y700 and Y774 (Andoniou et al. 1996), binding with Vav is mediated by Y770 (Marengere et al 1997).
REACT_23856 (Reactome) Phosphorylated Shc recruits Grb2 and Gab2, probably by binding to Grb2 in the Grb2:Gab2 complex. Gab2 associates with Grb2, Shc, Shp2 and the p85 subunit of PI3K (Gu et al. 1998). The association of Grb2 with Gab2 has been suggested to be constitutive (Gu et al. 2000, Kong et al. 2003, Harkiolaki et al. 2009), so Gab2 may be recruited to Shc1 with Grb2. Alternatively, Gab2 has been suggested to associate constitutively with Shc (Kong et al 2003). In either case, the result is a complex of Shc:Grb2:Gab2. Gab2 binding to p85 (Gu et al. 1998) links Shc1 to PI3K activity and subsequent activation of kinases such as Akt (Gu et al. 2000).
REACT_23857 (Reactome) Upon receptor activation, Shc is recruited to the receptor complex, where it becomes tyrosine phosphorylated. The recruitment of Shc is mediated by Y593 (Y577 in the mature peptide) of the common beta chain (Bc), which binds the PTB domain of Shc (Pratt et al. 1996). Phosphorylated Shc interacts with Grb2 within a Grb2:Gab2 complex, promoting tyrosine phosphorylation of Gab2. The p85 subunit of PI3Kinases associates with phosphorylated Gab, and this induces activation of the catalytic p110 PI3K subunit leading to activation of Akt kinase, thereby regulating cell survival and/or proliferation.
REACT_23861 (Reactome) Immunoprecipitation and kinase activity experiments demonstrated that Ser-585 phosphorylation of the common beta chain (Bc) was required for activation of PI3K activity in response to IL-3 and co-precipitation of Bc, 14-3-3 zeta and the p85 subunit of Class 1A PI3 kinases (Guthridge et al. 2000). Subsequent experiments confirmed that Ser-585 phosphorylation and PI3K activation are required to promote cell survival in response to GM-CSF, but not for proliferation responses, and that this mechanism is independent of Bc tyrosine phosphorylation (Guthridge et al. 2004). This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors; the other involves Bc tyrosine-593 phosphorylation-mediated recruitment of SHC1, GRB2 and GAB2.
REACT_23864 (Reactome) Human IL-5 is a disulphide-linked homodimer with 115 amino-acid residues in each chain.
REACT_23869 (Reactome) Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl-B targets PI3K for ubiquitination and degradation in T cells (Fang et al. 2000). Similarly, Cbl activation by tyrosine phosphorylation increases PI3K ubiquitination and proteasomal degradation (Dufour et al. 2008).
REACT_23870 (Reactome) The common beta chain (Bc), binds 14-3-3 zeta at a site that requires phosphorylation of Serine 585 (Stomski et al. 1999). Bc modifications that prevent Ser-585 phosphorylation do not recruit 14-3-3 zeta (Guthridge et al. 2000).
REACT_23874 (Reactome) SHIP dephosphorylates PIP3 and may limit the magnitude or duration of signaling events that are dependent upon PIP3-mediated membrane recruitment of plextrin homology (PH) domain signalling proteins such as PI3K and Akt (Aman et al. 1998). The PTB domain of SHC1 binds to phosphorylated tyrosine residues on SHIP. Mutations that inactivate the PTB domain prevent this binding and substitution of F for Y917 and Y1020 on SHIP prevents creation of the phosphotyrosine motifs that are recognized by the SHC1 PTB domain, blocking the interaction (Lamkin et al. 1997). A functional SHIP SH2 domain is also reported as a requirement for association of SHIP with Shc (Liu et al. 1997). GRB2 stabilizes the SHC1/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on SHC1, forming a ternary complex of SHC1:GRB2:SHIP described as inducible by IL-3, IL-5 or GM-CSF by many authors (Jucker et al. 1997, Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999).
REACT_23875 (Reactome) The alpha subunit of the GM-CSF receptor binds GM-CSF with relatively low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of GM-CSF with the alpha chain to form a binary complex. This binary complex is then able to bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008).
REACT_23884 (Reactome) Activated JAK2 binds to unphosphorylated STAT5; cytokine treatment of cells leads to JAK2 activation and promotes binding of JAK2 to unphosphorylated STAT5.


STAT5 proteins are considered the main targets of IL-3, IL-5 and GM-CSF signaling (Mui et al. 1995a, Mui et al. 1995b, Ihle, 2001), but other members of this family including STAT3 and STAT1 (Chin et al. 1996) can be involved, the STAT family member activated appears to depend on the cell line used in the study, rather than the cytokine (Reddy et al. 2000). IL-5 and GM-CSF increase STAT3 and 5 signaling (Caldenhoven et al. 1995, Stout et al. 2004).


Unphosphorylated STATs are cytoplasmic; tyrosine phosphorylation facilitates dimerization and translocation to the nucleus where they act as transcription factors. STATs were originally described as ligand-induced transcription factors in interferon-treated cells, subsequently they were shown to be critical in many signal transduction pathways associated with cytokines and neurokines including several interleukins, the interferons, erythropoietin, prolactin, growth hormone, oncostatin M (OSM), and ciliary neurotrophic factor (Darnell 1997, Reddy et al. 2000). JAK-STAT signaling is widely accepted as a primary signaling route for receptors that share the common beta subunit (Bc).
The role of the receptor itself in STAT5 binding is somewhat controversial because while STAT proteins can be recruited to tyrosine phosphorylated receptors via their SH2 domains (Greenlund et al. 1995, Li et al. 1997) binding of STAT5 to Bc has not been formally demonstrated (Guthridge et al. 1998), though tyrosine-phosphorylated peptides of Bc have been demonstrated to associate with STAT5, and anti-Bc or phosphotyrosine antibodies inhibited GM-CSF induced STAT5 DNA binding activity (Sakurai et al. 2000). Binding of JAK2 to STAT5 can occur in vitro when no receptor is present (Flores-Morales et al. 1998). STAT5 activation was seen when all six conserved cytoplasmic tyrosines in Bc were mutated to P (Okuda et al. 1997), but a C-terminal deletion mutant of Bc while able to activate JAK2 was unable to activate STAT5 (Smith et al. 1997). These observations suggest that JAK2 activation is a critical step in STAT signaling from Bc-containing receptors, but other factors may be required. It is not clear whether Bc is directly involved or not in STAT5 activation, but the specificity for particular STAT members is believed to be determined by STAT docking sites present on the receptor molecules, not JAK kinase preference (Reddy et al. 2000).
REACT_23896 (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 believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000).
REACT_23911 (Reactome) Grb2 stabilizes the Shc/SHIP complex (Harmer & DeFranco 1999), presumably by simultaneously binding via its SH3 domains to SHIP and via its SH2 domain to phosphotyrosines on Shc. This forms a ternary complex of SHC1:GRB2:SHIP described as an outcome of IL-3, IL-5 or GM-CSF stimulation (Lafrancone et al. 1995, Odai et al. 1997). SHIP2 also associates with SHC1 but does not appear to require Grb2 for stability (Wisniewskiet al. 1999).
REACT_23912 (Reactome) Upon ligand binding to the alpha subunit, the alpha and Bc subunits asociate, forming a high affinity receptor. Subsequent signaling may require a disulfide-linked association between the alpha and beta chains (Stomski et al. 1996). While the formation of a 1:1:1 complex of interleukin:alpha subunit:common beta subunit represents a high-affinity binding complex, receptor activation involves the formation of higher order multimeric structures. The stoichiometry of endogenous active receptor complexes is not clear, but studies using dominant-negative, chimeric, and mutant receptors and modeling studies all suggest that a minimum of two Bc subunits are required for receptor activation and signaling (Guthridge et al. 1998, Hansen et al. 2008).

The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One such site is Y766, numbered according to the Uniprot canonical sequence. Note that in many publications this position is numbered as 750, referring to the mature sequence with signal peptide removed. These phosphorylations are mediated by receptor-associated kinases with JAK2 as the most likely candidate (Quelle et al. 1994, Guthridge et al. 1998). Specific phosphorylations appear to mediate association with different signaling components (Sato et al. 1993), e.g. substitution of F for Y766 prevents Shc phosphorylation (Inhorn et al. 1995) but not JAK2 phosphorylation. Modeling and structural data suggest that the active receptor is at least a dimer of ligand:alpha subunit:common beta subunit complexes (Bagley et al. 1997, Guthridge et al. 1998, Hansen et al. 2008). This fits a model of receptor activation whereby dimerization leads to Jak2 activation by transphosphorylation of the activation sites (Ihle et al. 1995, Guthridge et al. 1998, Hansen et al. 2008), leading to Bc activation by phosphorylation. The active receptors are represented here as dimers of ligand:alpha subunit:common beta subunit complexes.
REACT_23914 (Reactome) IL3 stimulation induces rapid and transient tyrosine-phosphorylation of Vav and the binding of Vav to Tec kinase through Tec homology domains. (Machide et al. 1995). Vav1 and Tec were seen to associate into a complex with the activated prolactin receptor (Kline et al. 2001). These reports were interpreted as Tec enhancing Vav GEF activity, but it has been suggested that Vav might contribute to Tec activation in T cell signaling (Reynolds et al. 2002). Tec kinases generally require PI3K-dependent membrane translocation and phosphorylation of the kinase domain, often by an Src family kinase, for activation (Takesono et al. 2002).
REACT_23919 (Reactome) The GM-CSF receptor alpha subunit has a single transmembrane domain, a glycosylated extracellular domain and a short (54 amino acids) cytoplasmic tail, containing no tyrosine kinase domain (Gearing et al. 1989). It binds GM-CSF with a relatively low affinity, and is not capable of signaling. The cytoplasmic domain of the alpha chain appears to be critical for GM-CSF signaling (Matsuguchi et al. 1997).
REACT_23925 (Reactome) The Crk adapter protein family is comprised of Crk-I and Crk-II, alternatively spliced products of a single gene with differing biological functions, and Crk-L, a distinct Crk-like gene product. Cbl is the dominant phosphoprotein associated with Crk in activated lymphocytes. In vitro binding indicates that the Crk SH2 domain binds Y774 of Cbl (Reedquist et al. 1996), leaving the SH3 domain of Crk free to interact with other SH3 domain-associated proteins.
REACT_23928 (Reactome) Recruitment of Sos1 to the receptor complex brings it into contact with membrane-associated Ras-GDP. Interactions with Ras modulate Sos1 activity in a two-step manner (McKay & Morrison, 2007). Sos1 acts as a guanine exchange factor for Ras (Chardin et al. 1993), activating the Ras-Raf-MAPK pathway.
REACT_23935 (Reactome) JAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.

Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation.
REACT_23939 (Reactome) The Interleukin-3 receptor alpha subunit (IL3Ra) has a single transmembrane domain, a glycosylated extracellular domain and a short (53 amino acids) cytoplasmic tail, containing no tyrosine kinase domain (Kitamura et al. 1991). It binds interleukin-3 with low affinity, and is not capable of signaling by itself.
REACT_23953 (Reactome) Phosphorylation of the receptor common beta chain (Bc) creates binding sites for proteins that trigger subsequent signaling cascades (Pawson & Scott, 1997). The cytoplasmic region of Bc contains several tyrosines that become phosphorylated on cytokine binding (Sorensen et al. 1989, Duronio et al. 1992, Sakamaki et al. 1992, Pratt et al. 1996). One site is Y766 (numbered as Y750 by Sakamaki et al. 1992 and many other publications). Phosphorylation of Bc in response to GM-CSF/IL3 is observed at low temperatures (4 degrees C) that prevent the phosphorylation of other proteins, suggesting that the kinase responsible is likely to be physically associated with the receptor complex prior to stimulation (Miyajima et al. 1993). JAK2 is activated in response to IL-3, IL-5 and GM-CSF but signaling via JAK/STAT is not dependent on Bc tyrosine phosphorylation (Okuda et al. 1997). Based on these observations and the role of JAK1/3 in IL-2 signaling, JAK2 is believed to be the most likely candidate responsible for the phosphorylation of Bc (Guthridge et al. 1998). To represent the possible phosphorylation of Bc by kinases other than JAK2, this reaction includes receptor complexes with both active and inactive JAK2. Phosphorylation is represented only where this is necesssary for subsequent signaling; phosphorylation at other positions is probable.
REACT_23962 (Reactome) JAK2 associates with IL3 reecptor beta chain (IL3RB) better known as the cytokine recetpor common beta chain (Bc). This association was not found to be dependent upon, or influenced by, the presence of GM-CSF or the GM-CSF receptor alpha chain, suggesting that JAK2 and Bc may be constitutively associated (Quelle et al. 1994).
REACT_23965 (Reactome) SHP2 can associate with GRB2 (Stein-Gerlach et al. 1995). IL-3 induces the phosphorylation of SHP2 and its association with GRB2 (Welham et al. 1994). SHP2 may act as a scaffold protein to recruit other signaling molecules, e.g. SHP2 was reported to link GRB2 to the receptor tyrosine kinase c-kit (Tauchi et al. 1994).
REACT_23969 (Reactome) The Interleukin-5 receptor alpha subunit (IL5Ra) has a single transmembrane domain, a glycosylated extracellular domain and a short (58 amino acids) cytoplasmic tail, containing no tyrosine kinase domain. It binds IL-5 with a relatively low affinity and is not capable of signaling by itself. The alpha subunit has alternatively spliced soluble forms that are capable of binding IL-5 and act as natural antagonists of IL-5 signaling. The cytoplasmic domain of the alpha chain appears to be critical for IL-5 signaling (Takaki et al. 1993). IL5R alpha chain was found to be constitutively associated with JAK2 (Ogata et al. 1998); the same study found that JAK1 was constitutively associated with Bc, though the consensus is that JAK2 is associated with Bc.
REACT_23971 (Reactome) IL-3, IL-5 and GM-CSF all induce tyrosine phosphorylation of Shc (Dorsch et al. 1994). Three sites are known to mediate specific downstream associations; tyrosine Y427 (Salcini et al. 1994) mediates the subsequent association of Shc with Grb2 (Salcini et al. 1994). The identity of the kinase is unknown. Y349 and Y350 phosphorylation is not required for Ras-MAPK signaling but are involved in IL-3-induced cell survival (Gotoh et al. 1996).
Residue numbering used here refers to Uniprot P29353 where the p66 isoform has been selected as the canonical form. Literature references given here refer to the p52 isoform which lacks the first 110 residues, so Y427 is referred to as Y317 in Salcini et al. 1994, Y349 and Y350 as Y239 and Y240 in Gotoh et al. 1996.
REACT_23989 (Reactome) Cbl and Vav interact in thymocytes and peripheral T cells (Marengere et al. 1997). Cbl phosphorylated at Y700 binds Vav1 in 293T cells, leading to Vav ubiquitinylation and proteolytic degradation.
REACT_23992 (Reactome) The alpha subunit of the IL5 receptor binds IL-5 with relatively low affinity. Binding of this dimer to the common beta subunit (Bc) confers high affinity binding. Recent models of receptor activation suggest a sequential activation that is initiated by the low-affinity interaction of ligand with the alpha chain to form a binary complex. This binary complex may bind preformed Bc dimers generating a 2:2:2 hexameric complex (Hansen et al. 2008).
REACT_23998 (Reactome) Cbl binds B-cell linker protein, a molecular scaffold bridging Syk to downstream signaling pathways by recruiting signaling molecules, such as Btk, phospholipase C gamma 2, Vav, and Grb2 to the cell membrane to form a signalosome complex. Cbl is believed to negatively regulate signaling from this complex. Consistent with this, Cbl inactivation reverses a number of critical defects in early B cell differentiation seen in BLNK-deficient mice (Song et al. 2007).
REACT_23999 (Reactome) GM-CSF and IL-3 application lead to Ser-585 phosphorylation of the Common beta chain (Bc) shared with the IL-3 and IL-5 receptors (Stomski et al. 1999, Guthridge et al. 2000). PKA was identified as capable of phosphorylating Bc at S585 (Guthridge et al. 2000).
REACT_24014 (Reactome) The common beta chain (Bc) has at least at least one direct binding site for SHP-1/SHP-2 (PTPN6/PTPN11). The SH2 domains of SHP1 and SHP2 associate with Y628 of Bc following IL-3 stimulation (Pei et al. 1994, Bone et al. 1997). SHPs act as regulators of signaling. SHP1 is thought to be a negative regulator of growth that terminates signals. Binding of SHP1 to EpoR leads to SHP1 activation and dephosphorylation of JAK2, terminating proliferative signals (Klingmuller et al. 1995). SHP1 has also been shown to interact directly and dephosphorylate JAK2 (Jiao et al. 1996). Although SHP-2 competes for the same binding site, it is thought to be a positive modulator. SHP2 associates with JAK1/2 and is phosphorylated at Y304 by these kinases, creating a GRB2 recognition motif (Yin et al. 1997). IL-3 induces the phosphorylation of SHP2 and its association with Grb2 (Welham et al. 1994). SHP2 could thereby act as an adaptor between Bc and Grb2 leading to activation of the ras/mitogen-activated protein kinase pathway. SHP2 can also associate with the p85 subunit of phosphatidylinositol 3-kinase (Welham et al. 1994) so SHP2 may also regulate this pathway.
REACT_24024 (Reactome) Shc promotes Gab2 tyrosine phosphorylation via Grb2 (Gu et al. 2000). This promotes binding of Gab2 to p85alpha, a component of Class 1A PI3Ks (Gu et al. 1998). JAK1 may also be involved in PI3K recruitment (Migone et al. 1998). Binding of p85 activates PI3K kinase activity, with consequent effects on many processes including Akt activation. This is one of two mechanisms described for the recruitment of PI3K to the IL-3/IL-5/GM-CSF receptors, the other is mediated by Serine-585 phosphorylation of the common beta chain.
SHC1REACT_23857 (Reactome)
SHIP1,2REACT_23874 (Reactome)
SHP-2/SHP-1REACT_24014 (Reactome)
STAT5REACT_23884 (Reactome)
TECREACT_23914 (Reactome)
Tyrosine kinases that phosphorylate the Common beta chainREACT_23953 (Reactome)
VAV1REACT_23914 (Reactome)
VAV1REACT_23989 (Reactome)
YWHAZREACT_23870 (Reactome)
p-STAT5A/BArrowREACT_23896 (Reactome)
p-Y700,Y731,Y774-CBLREACT_23925 (Reactome)
p-Y700,Y731,Y774-CBLREACT_23989 (Reactome)
p-Y700,Y731,Y774-CBLREACT_23998 (Reactome)
p85-containing Class 1A PI3KsREACT_23799 (Reactome)
p85-containing Class 1A PI3KsREACT_23861 (Reactome)
p85-containing Class 1A PI3KsREACT_24024 (Reactome)
pREACT_23785 (Reactome)
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