FLT3 signaling (Homo sapiens)

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D586_E587insEYFYVDFREY GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion SPTBN1(2-159)-p-6Y FLT3(570-993) fusion ZMYM2(1-1057)-FLT3(586-993) fusion S-Farn-Me KRAS4B p-6Y FLT3 E598_Y599insVDFREYE UBC(305-380) PIK3R1 p-6Y FLT3 Y589_F590insFYVDFREYEYDLKWEF STAT5type II FLT3-bindingTKIsp-6Y FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL FLT3LGdimer:FLT3:FLT3-binding type I TKIsp-Y-GAB2 UBC(533-608) GAB2FLT3LG FLT3LG GTPp-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKW SH2B3SLA2 FLT3LG p-6Y FLT3 E598_Y599insFYVDFREY STAT5A ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion p-6Y FLT3 Y591_V592insVDFREYEYDH BCL2L1PIK3R1 Ub-pY FLT3 SOCS2p-6Y FLT3 Y591_V592insVDFREDREHH ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion PTPN11 ETV6(1-384)-p-6Y FLT3(573-993) fusion S-Farn-Me KRAS4B p-6Y FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE p-Y-GAB2 ETV6(1-384)-p-6Y FLT3(573-993) fusion p-Y694-STAT5A ETV6(1-301)-p-6Y FLT3(574-993) fusion FLT3LG dimer:FLT3p-6Y FLT3 E598_Y599insFYVDFREY p-6Y FLT3 K602_W603insYEYDLK GTP PTPN11 ETV6(1-301)-p-6Y FLT3(574-993) fusion active FLT3:p-YGRB10p-6Y FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE GRB2-1 active FLT3:LCKp-Y-GAB2 FLT3LG active FLT3:CBLp-Y GRB10 BCL2L1 gene Autophosphorylated FLT3 kinase domain mutants of FLT3 active FLT3:GRAP2GRB2-1 PTPRJp-Y FLT3 fusiondimersS-Farn-Me PalmS NRAS FLT3LG p-Y699-STAT5B GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion ATPFLT3LG Active FLT3:HCKETV6(1-301)-p-6Y FLT3(574-993) fusion p-STAT5A, p-STAT5BGRB10 PTPN11 p-Y694-STAT5A active FLT3:p-YGRB10:PI3KTRIP11(2-1724)-p-4Y FLT3(594-993) fusion FLT3 S451F p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKW p-Y-GAB2 GRAP2FLT3LG FLT3LG dimerAutophosphorylated FLT3 S-Farn-Me-2xPalmS HRAS Autophosphorylated FLT3 Active FLT3:GRB2:p-YGAB2:PI3KFLT3 p-STAT5p-Y-CBL SOCS2 FLT3LG dimer:FLT3dimerSPTBN1(2-159)-p-6Y FLT3(570-993) fusion p-6Y FLT3 F612_G613insGYVDFREYEYDLKWEFRPRENLF active FLT3:SOCS6p-6Y FLT3 L610_E611insLKWEFPRENL p-6Y FLT3 Y599_F600insFYVDFREYEYDLKWEF ABL2S-Farn-Me PalmS NRAS Autophosphorylated FLT3 TRIP11(2-1724)-p-4Y FLT3(594-993) fusion BCL2L11TRIP11(2-1724)-FLT3(594-993) fusion Autophosphorylated FLT3 ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion p-6Y juxtamembrane domain mutant dimers of FLT3 GOLGB1(1-2893)-FLT3(591-993) fusion SPTBN1(2-159)-p-6Y FLT3(570-993) fusion ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion p-6Y FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE p-6Y FLT3 E598_Y599insFDFREYE ATPp-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKWEFPREN p-Y-GAB2 active FLT3:SOCS2GRB2-1 PIK3CA S-Farn-Me-PalmS KRAS4A STAT5B p-6Y FLT3 I836LInsD NOX4 geneCDKN1AETV6(1-384)-p-3Y FLT3(659-1620) fusion ETV6(1-384)-p-3Y FLT3(659-1620) fusion ZMYM2(1-1059)-FLT3(594-993) fusion p-6Y FLT3 Y599_F600insFYVDFREYEYDLKWEF p-Y GRB10 active FLT3:SH2B3UBB(1-76) p-STAT5:CDKN1A genep-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKWEFPREN p-6Y FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion FLT3LG TRIP11(2-1724)-p-4Y FLT3(594-993) fusion FLT3 fusion dimersAutophosphorylated FLT3 ETV6(1-384)-FLT3(573-993) fusion GRB2 p21 RAS:GDPFLT3LG UBC(381-456) ETV6(1-301)-p-6Y FLT3(574-993) fusion ETV6(1-384)-p-3Y FLT3(659-1620) fusion Autophosphorylated FLT3 Autophosphorylated FLT3 GRB2-1 p-6Y FLT3 Y591_V592insVDFREYEYDH p-6Y FLT3 Y589_F590insFYVDFREYEYDLKWEF FLT3LG p-Y699-STAT5B p-6Y FLT3 ITD mutantdimers:GRB2:p-YGAB2:PTPN11:p-STAT5p-6Y FLT3 E598_Y599insYDLKWEFRRENLEFG PIK3R1 p-6Y FLT3 L601_K602insREYEYDL H2Op-6Y FLT3 K602_W603insYEYDLK FLT3LG PTPN11 PIK3R1 Autophosphorylated FLT3 juxtamembrane domain mutants of FLT3 FOXO3p-Y699-STAT5B ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion p-6Y FLT3 F612_G613insGYVDFREYEYDLKWEFRPRENLF SOCS6PIP3 activates AKTsignalingp-Y694-STAT5A UBC(609-684) p-6Y FLT3 Y599_F600insFYVDFREYEYDLKWEF Active FLT3:FYNp-6Y FLT3 E598_Y599insYDLKWEFRRENLEFG ETV6(1-154insGSFILG)-FLT3(573-993) fusion ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion active FLT3:pY-CBLPIK3R1 SPTBN1(2-159)-FLT3(570-993) fusion ETV6(1-301)-p-6Y FLT3(574-993) fusion CDKN1A geneADPAutophosphorylated FLT3 GRB2-1 ETV6(1-384)-p-3Y FLT3(659-1620) fusion S-Farn-Me-PalmS KRAS4A p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKW p-Y694-STAT5A ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion SPTBN1(2-159)-p-6Y FLT3(570-993) fusion PTPN11:p-STAT5MYO18A(1-1462)-p-4Y FLT3(595-993) fusion SOCS6 p-6Y FLT3 L601_K602insREYEYDL ZMYM2(1-1057)-FLT3(586-993) fusion TRIP11(2-1724)-p-4Y FLT3(594-993) fusion ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion p-6Y FLT3 E598_Y599insFDFREYE p-6Y FLT3 I836LInsD p-Y-GAB2 active FLT3:GRB10SOCS2 p-6Y FLT3 L610_E611insLKWEFPRENL p-T32,S253,S315-FOXO3p-6Y FLT3 A627E_T628insYEYDLKWEFPRENLEFGKVLGSGAFGKVMNA Autophosphorylated FLT3 PIK3CA ETV6(1-384)-FLT3(573-993) fusion FLT3:FLT3-bindingtype II TKIsp-T305,S472-AKT3 p-6Y FLT3 Y600_D601insGLYVDFREYEY SOCS6 UBC(457-532) S-Farn-Me-2xPalmS HRAS FLT3LG Ub-pY FLT3 FLT3 extracellulardomain, kinasedomain andjuxtamembranedomain mutantsp-Y-CBL ADPp-6Y FLT3 E598_Y599insYDLKWEFRRENLEFG ETV6(1-301)-FLT3(574-993) fusion ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion p-6Y FLT3 L601_K602insREYEYDL p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKW p-T32,S253,S315-FOXO3GRB2 p-6Y FLT3 E598_Y599insFYVDFREY FLT3 FLT3 fusion proteinsp-Y FLTfusions:GRB2:p-YGAB2:PI3KR1p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKWEFPREN GRB2-1 p-6Y FLT3 D600_L601insMGMGGECNPGRQ kinase domain mutant dimers of FLT3 MYO18A(1-1462)-p-4Y FLT3(595-993) fusion SPTBN1(2-159)-FLT3(570-993) fusion p-6Y FLT3 A627E_T628insYEYDLKWEFPRENLEFGKVLGSGAFGKVMNA p-6Y FLT3 F594_R595insREYEYDL UBC(1-76) p-Y699-STAT5B MYO18A(1-1462)-p-4Y FLT3(595-993) fusion p-6Y FLT3 E598_Y599insVDFREYE ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion p-Y768,Y969 FLT3dimer:FLT3LG dimerp-Y699-STAT5B BCL2L1 geneLCK GRB10ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion TRIP11(2-1724)-p-4Y FLT3(594-993) fusion p-6Y FLT3 D600_L601insMGMGGECNPGRQ SPTBN1(2-159)-p-6Y FLT3(570-993) fusion p-6Y FLT3 E598_Y599insFDFREYE Autophosphorylated FLT3 SOS1 RAF/MAP kinasecascadePIK3R1p-6Y FLT3 L610_E611insLKWEFPRENL FLT3LG p-6Y FLT3 Y600_D601insGLYVDFREYEY PiAutophosphorylated FLT3 p-6Y FLT3 S451F Autophosphorylated FLT3 ETV6(1-301)-FLT3(574-993) fusion ADPUBC(153-228) p-Y FLT3fusions:GRB2:SOS1TRIP11(2-1724)-FLT3(594-993) fusion Active FLT3:PTPN11FLT3LG ETV6(1-384)-p-3Y FLT3(659-1620) fusion FLT3LG ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion MYO18A(1-1462)-FLT3(595-993) fusion ADPFLT3LG ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion NADPHp-6Y FLT3 Y591_V592insVDFREYEYDH ATPp-6Y FLT3 Y599_F600insFYVDFREYEYDLKWEF p-Y768,Y969 FLT3 p-6Y FLT3 Y591_V592insVDFREDREHH FLT3LG ZMYM2(1-1059)-FLT3(594-993) fusion p-6Y FLT3 D586_E587insEYFYVDFREY GRB2-1 ETV6(1-384)-p-6Y FLT3(573-993) fusion p21 RAS:GTPp-Y-GAB2 FLT3 p-Y699-STAT5B ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion NOX4 gene p-6Y FLT3 K602_W603insYEYDLK Active FLT3: GRB2p-6Y FLT3 F594_R595insREYEYDL GRB2 ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion p-6Y FLT3 Y591_V592insVDFREDREHH p-Y FLT3fusions:GRB2:p-YGAB2ADPp-6Y FLT3 E598_Y599insFDFREYE p-6Y FLT3 D600_L601insMGMGGECNPGRQ Autophosphorylated FLT3 CBL ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion p-Y-GAB2 ADPETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion FLT3LG juxtamembrane domain mutant dimers of FLT3 FLT3LG type I FLT3-bindingTKIsETV6(1-384)-FLT3(569-993) fusion UBB(153-228) p-6Y FLT3 L610_E611insLKWEFPRENL MYO18A(1-1462)-p-4Y FLT3(595-993) fusion SLA p-6Y FLT3 Y589_F590insFYVDFREYEYDLKWEF p-Y694-STAT5A H+p-Y FLT3fusions:GRB2:p-YGAB2:PI3KAutophosphorylated FLT3 NOX4 gene:p-STAT5GAB2 Active FLT3FLT3LG p-Y GRB10 PIK3R1 FLT3 extracellulardomain, kinasedomain andjuxtamembranedomain mutantdimersactive FLT3:SLA2p-6Y FLT3 D586_E587insEYFYVDFREY p-6Y FLT3 K602_W603insYEYDLK ActiveFLT3:GRB2:p-Y-GAB2:PIK3R1UBC(77-152) STAT5B UBA52(1-76) MYO18A(1-1462)-p-4Y FLT3(595-993) fusion PTPN11:p-STAT5active FLT3:SLAATPp-Y694-STAT5A p-6Y FLT3 E598_Y599insVDFREYE NADP+ActiveFLT3:GRB2:p-Y-GAB2:PTPN11p-6Y FLT3 A627E_T628insYEYDLKWEFPRENLEFGKVLGSGAFGKVMNA FLT3LG p-6Y FLT3 E598_Y599insFYVDFREY ETV6(1-301)-p-6Y FLT3(574-993) fusion p-6Y FLT3 ITD mutantdimers:GRB2:p-YGAB2:PTPN11FLT3 S451F FLT3LG GRB2-1 Autophosphorylated FLT3 CSKFLT3LG active FLT3:SYKUBC(229-304) p-Y694-STAT5A GDPUBB(77-152) p-6Y FLT3 F612_G613insGYVDFREYEYDLKWEFRPRENLF ActiveFLT3:GRB2:p-Y-GAB2ATPp-6Y FLT3 F594_R595insREYEYDL FLT3Autophosphorylated FLT3 p-6Y FLT3 D600_L601insMGMGGECNPGRQ FLT3LG TRIP11(2-1724)-p-4Y FLT3(594-993) fusion active FLT3:ABL2GAB2 ADPActiveFLT3:GRB2:SOS1LCKZMYM2(1-1057)-p-5Y FLT3(586-993) fusion ABL2 p-Y-GAB2 p-6Y FLT3 F612_G613insGYVDFREYEYDLKWEFRPRENLF ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion MYO18A(1-1462)-FLT3(595-993) fusion SH2B3 ETV6(1-301)-p-6Y FLT3(574-993) fusion ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion p-6Y FLT3 I836LInsD p-Y694-STAT5A PIM1p-6Y FLT3 E598_Y599insYDLKWEFRRENLEFG p-Y699-STAT5B SPTBN1(2-159)-p-6Y FLT3(570-993) fusion ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion FLT3LG FLT3LG CBLGOLGB1(1-2893)-FLT3(591-993) fusion ETV6(1-384)-p-6Y FLT3(573-993) fusion FLT3LG Autophosphorylated FLT3 p-6Y FLT3 Y591_V592insVDFREDREHH ATPUbETV6(1-384)-p-3Y FLT3(659-1620) fusion SOS1 Autophosphorylated FLT3 Autophosphorylated FLT3 ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion FLT3LG H2O2HCKETV6(1-384)-p-6Y FLT3(573-993) fusion GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion GDP PIK3CAp-6Y FLT3 Y600_D601insGLYVDFREYEY NOX4O2FLT3LG p-6Y FLT3 D586_E587insEYFYVDFREY CSK p-6Y FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE SLAETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion ETV6(1-384)-p-3Y FLT3(659-1620) fusion p-6Y FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL p-Y694-STAT5A ETV6(1-384)-p-6Y FLT3(573-993) fusion MYO18A(1-1462)-p-4Y FLT3(595-993) fusion ATPGRB2-1FLT3LG p-6Y kinase domain mutant dimers of FLT3 GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion SLA2p-T309,S474-AKT2 GRB2 PTPN11 ADPFLT3LG ActiveFLT3:GRB2:GAB2p-T,p-S-AKTPTPN11Autophosphorylated FLT3 ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion p-Y FLT3fusions:GRB2:GAB2FYNp-6Y FLT3 F594_R595insREYEYDL GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion ETV6(1-384)-p-6Y FLT3(573-993) fusion GRB2-1 ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion TRIP11(2-1724)-p-4Y FLT3(594-993) fusion Autophosphorylated FLT3 p-Y FLT3fusions:p-STAT5ADPCDKN1B geneSYK MYO18A(1-1462)-p-4Y FLT3(595-993) fusion SPTBN1(2-159)-p-6Y FLT3(570-993) fusion Autophosphorylated FLT3 ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion ETV6(1-301)-p-6Y FLT3(574-993) fusion ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion Autophosphorylated FLT3 p-6Y FLT3 L601_K602insREYEYDL p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKWEFPREN p-Y-GAB2 CDKN1A gene p-6Y FLT3 A627E_T628insYEYDLKWEFPRENLEFGKVLGSGAFGKVMNA p-Y699-STAT5B RPS27A(1-76) Autophosphorylated FLT3 GRAP2 GRB2-1 SYKETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion CDKN1BSTAT5A active FLT3:p-YGRB10:PIK3R1ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion SPTBN1(2-159)-p-6Y FLT3(570-993) fusion FLT3 E3 ubiquitinligasesETV6(1-384)-FLT3(569-993) fusion Ub-pY FLT3:FLT3LGdimerp-Y-GAB2 p-6Y FLT3extracellulardomain, kinasedomain andjuxtamembranedomain mutantdimersp-6Y FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL p-Y699-STAT5B GRB2-1 p-6Y FLT3 ITD mutantdimers:GRB2:p-YGAB2ETV6(1-384)-p-6Y FLT3(573-993) fusion FLT3LG FLT3LG GRB2-1 FLT3LG p-6Y FLT3 Y591_V592insVDFREYEYDH PTPN11 p-6Y FLT3 E598_Y599insVDFREYE SOS1MYO18A(1-1462)-p-4Y FLT3(595-993) fusion BCL2L11 genep-6Y FLT3 Y589_F590insFYVDFREYEYDLKWEF BCL2L1gene:PTPN11:p-STAT5PTPN11 p-6Y FLT3 I836LInsD HCK ATPETV6(1-384)-p-3Y FLT3(659-1620) fusion p-Y88-CDKN1BGRB2-1 p-T308,S473-AKT1 PTPN11 active FLT3:CSKFYN PIK3CA Ub-pY FLT3:FLT3LGdimerAutophosphorylated FLT3 p-6Y FLT3 Y600_D601insGLYVDFREYEY p-Y FLT3 fusiondimers:GRB2TRIP11(2-1724)-p-4Y FLT3(594-993) fusion ETV6(1-338insGCS)-FLT3(573-993) fusion 211319133511111124, 81612111121602413353566, 1151911454356013546635543546, 104215446, 104542161666146, 10421545446, 1046713, 60, 676666606611435213519355466, 1156115111196666, 11595355435601311166, 11560191116011154676635616611166215411195356722, 26-28, 30...217046, 1047054242172, 83, 104, 1146654115571114095111955466541935676611146, 1042495669521133567136735352166215767111602161666167601919951061119519134011119217067139521215711111554111703595545446, 1046666211142111111135672495211146621666011595212160541335601152161546146, 10461661114040


Description

Feline McDonough Sarcoma-like tyrosine kinase (FLT3) (also known as FLK2 (fetal liver tyrosine kinase 2), STK-1 (stem cell tyrosine kinase 1) or CD135) is a member of the class III receptor tyrosine kinase family involved in the differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Upon FLT3 ligand (FL) binding, the receptor forms dimers and is phosphorylated. Consequently, adapter and signaling molecules bind with the active receptor and trigger the activation of various pathways downstream including PI3K/Akt and MAPK cascades (Grafone T et al. 2012). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9607240
Reactome-version 
Reactome version: 75

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Bibliography

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History

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CompareRevisionActionTimeUserComment
129740view01:54, 22 May 2024EweitzModified title
115094view17:04, 25 January 2021ReactomeTeamReactome version 75
113536view12:01, 2 November 2020ReactomeTeamReactome version 74
112837view18:43, 9 October 2020DeSlOntology Term : 'kinase mediated signaling pathway' added !
112782view16:18, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ABL2 ProteinP42684 (Uniprot-TrEMBL)
ABL2ProteinP42684 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Active FLT3:GRB2:GAB2ComplexR-HSA-9606619 (Reactome)
Active FLT3:GRB2:SOS1ComplexR-HSA-9607300 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PIK3R1ComplexR-HSA-9607223 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PTPN11ComplexR-HSA-9606788 (Reactome)
Active FLT3:GRB2:p-Y-GAB2ComplexR-HSA-9606627 (Reactome)
Active FLT3: GRB2ComplexR-HSA-9604756 (Reactome)
Active FLT3:FYNComplexR-HSA-9605257 (Reactome)
Active FLT3:GRB2:p-Y GAB2:PI3KComplexR-HSA-9698169 (Reactome)
Active FLT3:HCKComplexR-HSA-9609280 (Reactome)
Active FLT3:PTPN11ComplexR-HSA-9604972 (Reactome)
Active FLT3ComplexR-HSA-9604751 (Reactome)
Autophosphorylated FLT3 ProteinP36888 (Uniprot-TrEMBL)
BCL2L1 gene:PTPN11:p-STAT5ComplexR-HSA-9698019 (Reactome)
BCL2L1 gene ProteinENSG00000171552 (Ensembl)
BCL2L1 geneGeneProductENSG00000171552 (Ensembl)
BCL2L11 geneGeneProductENSG00000153094 (Ensembl)
BCL2L11ProteinO43521 (Uniprot-TrEMBL)
BCL2L1ProteinQ07817 (Uniprot-TrEMBL)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CDKN1A gene ProteinENSG00000124762 (Ensembl)
CDKN1A geneGeneProductENSG00000124762 (Ensembl)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B geneGeneProductENSG00000111276 (Ensembl)
CDKN1BProteinP46527 (Uniprot-TrEMBL)
CSK ProteinP41240 (Uniprot-TrEMBL)
CSKProteinP41240 (Uniprot-TrEMBL)
ETV6(1-154insGSFILG)-FLT3(573-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-154insGSFILG)-p-6Y FLT3(573-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-301)-FLT3(574-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-301)-p-6Y FLT3(574-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-338insGCS)-FLT3(573-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-338insGCS)-p-6Y FLT3(573-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-384)-FLT3(569-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-384)-FLT3(573-993) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-384)-p-3Y FLT3(659-1620) fusion ProteinP41212 (Uniprot-TrEMBL)
ETV6(1-384)-p-6Y FLT3(573-993) fusion ProteinP41212 (Uniprot-TrEMBL)
FLT3 E3 ubiquitin ligasesComplexR-HSA-9706228 (Reactome)
FLT3 ProteinP36888 (Uniprot-TrEMBL)
FLT3 S451F ProteinP36888 (Uniprot-TrEMBL)
FLT3 extracellular

domain, kinase domain and juxtamembrane domain mutant

dimers		ComplexR-HSA-9695821 (Reactome)
FLT3 extracellular

domain, kinase domain and juxtamembrane

domain mutants		ComplexR-HSA-9695824 (Reactome)
FLT3 fusion dimersComplexR-HSA-9703409 (Reactome)
FLT3 fusion proteinsComplexR-HSA-9703345 (Reactome)
FLT3:FLT3-binding type II TKIsComplexR-HSA-9695792 (Reactome)
FLT3LG dimer:FLT3:FLT3-binding type I TKIsComplexR-HSA-9695796 (Reactome)
FLT3LG ProteinP49771 (Uniprot-TrEMBL)
FLT3LG dimer:FLT3 dimerComplexR-HSA-8854716 (Reactome)
FLT3LG dimer:FLT3ComplexR-HSA-6786754 (Reactome)
FLT3LG dimerComplexR-HSA-8854740 (Reactome)
FLT3ProteinP36888 (Uniprot-TrEMBL)
FOXO3ProteinO43524 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GAB2ProteinQ9UQC2 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GOLGB1(1-2893)-FLT3(591-993) fusion ProteinQ14789 (Uniprot-TrEMBL)
GOLGB1(1-2893)-p-5Y FLT3(591-993) fusion ProteinQ14789 (Uniprot-TrEMBL)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRAP2ProteinO75791 (Uniprot-TrEMBL)
GRB10 ProteinQ13322 (Uniprot-TrEMBL)
GRB10ProteinQ13322 (Uniprot-TrEMBL)
GRB2 ProteinP62993 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCK ProteinP08631 (Uniprot-TrEMBL)
HCKProteinP08631 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCKProteinP06239 (Uniprot-TrEMBL)
MYO18A(1-1462)-FLT3(595-993) fusion ProteinQ92614 (Uniprot-TrEMBL)
MYO18A(1-1462)-p-4Y FLT3(595-993) fusion ProteinQ92614 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NOX4 gene ProteinENSG00000086991 (Ensembl)
NOX4 gene:p-STAT5ComplexR-HSA-9698753 (Reactome)
NOX4 geneGeneProductENSG00000086991 (Ensembl)
NOX4ProteinQ9NPH5 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CAProteinP42336 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
PIM1 geneGeneProductENSG00000137193 (Ensembl)
PIM1ProteinP11309 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11:p-STAT5ComplexR-HSA-9697990 (Reactome)
PTPN11:p-STAT5ComplexR-HSA-9697993 (Reactome)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPRJProteinQ12913 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RPS27A(1-76) ProteinP62979 (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)
SH2B3 ProteinQ9UQQ2 (Uniprot-TrEMBL)
SH2B3ProteinQ9UQQ2 (Uniprot-TrEMBL)
SLA ProteinQ13239 (Uniprot-TrEMBL)
SLA2 ProteinQ9H6Q3 (Uniprot-TrEMBL)
SLA2ProteinQ9H6Q3 (Uniprot-TrEMBL)
SLAProteinQ13239 (Uniprot-TrEMBL)
SOCS2 ProteinO14508 (Uniprot-TrEMBL)
SOCS2ProteinO14508 (Uniprot-TrEMBL)
SOCS6 ProteinO14544 (Uniprot-TrEMBL)
SOCS6ProteinO14544 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
SPTBN1(2-159)-FLT3(570-993) fusion ProteinQ01082 (Uniprot-TrEMBL)
SPTBN1(2-159)-p-6Y FLT3(570-993) fusion ProteinQ01082 (Uniprot-TrEMBL)
STAT5 ActivationPathwayR-HSA-9645135 (Reactome) Signal transducer and activator of transcription (STAT) constitutes a family of universal transcription factors. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function in cell survival and proliferation. Several upstream signals including cytokines and growth factors can trigger STAT5 activation.
STAT5A ProteinP42229 (Uniprot-TrEMBL)
STAT5B ProteinP51692 (Uniprot-TrEMBL)
STAT5ComplexR-HSA-1295523 (Reactome)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYKProteinP43405 (Uniprot-TrEMBL)
TRIP11(2-1724)-FLT3(594-993) fusion ProteinQ15643 (Uniprot-TrEMBL)
TRIP11(2-1724)-p-4Y FLT3(594-993) fusion ProteinQ15643 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-pY FLT3 ProteinP36888 (Uniprot-TrEMBL)
Ub-pY FLT3:FLT3LG dimerComplexR-HSA-9706242 (Reactome)
Ub-pY FLT3:FLT3LG dimerComplexR-HSA-9706245 (Reactome)
UbComplexR-HSA-113595 (Reactome)
ZMYM2(1-1057)-FLT3(586-993) fusion ProteinQ9UBW7 (Uniprot-TrEMBL)
ZMYM2(1-1057)-p-5Y FLT3(586-993) fusion ProteinQ9UBW7 (Uniprot-TrEMBL)
ZMYM2(1-1059)-FLT3(594-993) fusion ProteinQ9UBW7 (Uniprot-TrEMBL)
ZMYM2(1-1059)-p-4Y FLT3(594-993) fusion ProteinQ9UBW7 (Uniprot-TrEMBL)
active FLT3:ABL2ComplexR-HSA-9706249 (Reactome)
active FLT3:CBLComplexR-HSA-9706252 (Reactome)
active FLT3:CSKComplexR-HSA-9706255 (Reactome)
active FLT3:GRAP2ComplexR-HSA-9706257 (Reactome)
active FLT3:GRB10ComplexR-HSA-9706260 (Reactome)
active FLT3:LCKComplexR-HSA-9706263 (Reactome)
active FLT3:SH2B3ComplexR-HSA-9706266 (Reactome)
active FLT3:SLA2ComplexR-HSA-9706273 (Reactome)
active FLT3:SLAComplexR-HSA-9706270 (Reactome)
active FLT3:SOCS2ComplexR-HSA-9706226 (Reactome)
active FLT3:SOCS6ComplexR-HSA-9706227 (Reactome)
active FLT3:SYKComplexR-HSA-9706276 (Reactome)
active FLT3:p-Y GRB10:PI3KComplexR-HSA-9706282 (Reactome)
active FLT3:p-Y GRB10:PIK3R1ComplexR-HSA-9706284 (Reactome)
active FLT3:p-Y GRB10ComplexR-HSA-9706279 (Reactome)
active FLT3:pY-CBLComplexR-HSA-9706224 (Reactome)
crenolanib
juxtamembrane domain mutant dimers of FLT3 R-HSA-9691148 (Reactome)
juxtamembrane domain mutants of FLT3 R-HSA-9691152 (Reactome)
kinase domain mutant dimers of FLT3 R-HSA-9682368 (Reactome)
kinase domain mutants of FLT3 R-HSA-9682396 (Reactome)
p-6Y FLT3

extracellular domain, kinase domain and juxtamembrane domain mutant

dimers		ComplexR-HSA-9695782 (Reactome)
p-6Y FLT3 A627E_T628insYEYDLKWEFPRENLEFGKVLGSGAFGKVMNA ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 D586_E587insEYFYVDFREY ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 D600_L601insMGMGGECNPGRQ ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 E598_Y599insFDFREYE ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 E598_Y599insFYVDFREY ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 E598_Y599insGLVQVTGSSDNEYFYVDFREYE ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 E598_Y599insVDFREYE ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 E598_Y599insYDLKWEFRRENLEFG ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 F594_R595insREYEYDL ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 F612_G613insGYVDFREYEYDLKWEFRPRENLF ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 I836LInsD ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:STAT5		ComplexR-HSA-9697982 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:p-STAT5		ComplexR-HSA-9697985 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11		ComplexR-HSA-9697970 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2		ComplexR-HSA-9702484 (Reactome)
p-6Y FLT3 K602_W603insYEYDLK ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 L601_K602insREYEYDL ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 L610_E611insCSSDNEYFYVDFREYEYDLKWEFPRENL ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 L610_E611insLKWEFPRENL ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKW ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 N609_L610insSSDNEYFYVDFREYEYDLKWEFPREN ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 S451F ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 Y589_F590insFYVDFREYEYDLKWEF ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 Y591_V592insVDFREDREHH ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 Y591_V592insVDFREYEYDH ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 Y599_F600insFYVDFREYEYDLKWEF ProteinP36888 (Uniprot-TrEMBL)
p-6Y FLT3 Y600_D601insGLYVDFREYEY ProteinP36888 (Uniprot-TrEMBL)
p-6Y juxtamembrane domain mutant dimers of FLT3 R-HSA-9691155 (Reactome)
p-6Y kinase domain mutant dimers of FLT3 R-HSA-9682374 (Reactome)
p-STAT5:CDKN1A geneComplexR-HSA-9698036 (Reactome)
p-STAT5A, p-STAT5BComplexR-HSA-507929 (Reactome)
p-STAT5ComplexR-HSA-1469978 (Reactome)
p-T,p-S-AKTComplexR-HSA-202072 (Reactome)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T32,S253,S315-FOXO3ProteinO43524 (Uniprot-TrEMBL)
p-Y FLT

fusions:GRB2:p-Y

GAB2:PI3KR1		ComplexR-HSA-9703358 (Reactome)
p-Y FLT3 fusions:GRB2:GAB2ComplexR-HSA-9703352 (Reactome)
p-Y FLT3 fusions:GRB2:SOS1ComplexR-HSA-9703349 (Reactome)
p-Y FLT3

fusions:GRB2:p-Y

GAB2:PI3K		ComplexR-HSA-9703369 (Reactome)
p-Y FLT3

fusions:GRB2:p-Y

GAB2		ComplexR-HSA-9703356 (Reactome)
p-Y FLT3 fusions:p-STAT5ComplexR-HSA-9703359 (Reactome)
p-Y FLT3 fusion dimers:GRB2ComplexR-HSA-9703378 (Reactome)
p-Y FLT3 fusion dimersComplexR-HSA-9703372 (Reactome)
p-Y GRB10 ProteinQ13322 (Uniprot-TrEMBL)
p-Y-CBL ProteinP22681 (Uniprot-TrEMBL)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y694-STAT5A ProteinP42229 (Uniprot-TrEMBL)
p-Y699-STAT5B ProteinP51692 (Uniprot-TrEMBL)
p-Y768,Y969 FLT3 dimer:FLT3LG dimerComplexR-HSA-9698407 (Reactome)
p-Y768,Y969 FLT3 ProteinP36888 (Uniprot-TrEMBL)
p-Y88-CDKN1BProteinP46527 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
ponatinib
type I FLT3-binding TKIsComplexR-ALL-9695790 (Reactome)
type II FLT3-binding TKIsComplexR-ALL-9695783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABL2R-HSA-9706287 (Reactome)
ADPArrowR-HSA-9604767 (Reactome)
ADPArrowR-HSA-9606622 (Reactome)
ADPArrowR-HSA-9695834 (Reactome)
ADPArrowR-HSA-9698005 (Reactome)
ADPArrowR-HSA-9699578 (Reactome)
ADPArrowR-HSA-9699579 (Reactome)
ADPArrowR-HSA-9703437 (Reactome)
ADPArrowR-HSA-9703438 (Reactome)
ADPArrowR-HSA-9706344 (Reactome)
ADPArrowR-HSA-9706350 (Reactome)
ATPR-HSA-9604767 (Reactome)
ATPR-HSA-9606622 (Reactome)
ATPR-HSA-9695834 (Reactome)
ATPR-HSA-9698005 (Reactome)
ATPR-HSA-9699578 (Reactome)
ATPR-HSA-9699579 (Reactome)
ATPR-HSA-9703437 (Reactome)
ATPR-HSA-9703438 (Reactome)
ATPR-HSA-9706344 (Reactome)
ATPR-HSA-9706350 (Reactome)
Active FLT3:GRB2:GAB2ArrowR-HSA-9606624 (Reactome)
Active FLT3:GRB2:GAB2R-HSA-9606622 (Reactome)
Active FLT3:GRB2:SOS1ArrowR-HSA-9607301 (Reactome)
Active FLT3:GRB2:SOS1mim-catalysisR-HSA-9607304 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PIK3R1ArrowR-HSA-9607224 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PIK3R1R-HSA-9698170 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PTPN11ArrowR-HSA-9606784 (Reactome)
Active FLT3:GRB2:p-Y-GAB2ArrowR-HSA-9606622 (Reactome)
Active FLT3:GRB2:p-Y-GAB2R-HSA-9606784 (Reactome)
Active FLT3:GRB2:p-Y-GAB2R-HSA-9607224 (Reactome)
Active FLT3: GRB2ArrowR-HSA-9604738 (Reactome)
Active FLT3: GRB2R-HSA-9606624 (Reactome)
Active FLT3: GRB2R-HSA-9607301 (Reactome)
Active FLT3:FYNArrowR-HSA-9605259 (Reactome)
Active FLT3:GRB2:p-Y GAB2:PI3KArrowR-HSA-9698170 (Reactome)
Active FLT3:HCKArrowR-HSA-9609274 (Reactome)
Active FLT3:PTPN11ArrowR-HSA-9604969 (Reactome)
Active FLT3ArrowR-HSA-9604767 (Reactome)
Active FLT3R-HSA-9604738 (Reactome)
Active FLT3R-HSA-9604969 (Reactome)
Active FLT3R-HSA-9605259 (Reactome)
Active FLT3R-HSA-9609274 (Reactome)
Active FLT3R-HSA-9698408 (Reactome)
Active FLT3R-HSA-9706287 (Reactome)
Active FLT3R-HSA-9706293 (Reactome)
Active FLT3R-HSA-9706298 (Reactome)
Active FLT3R-HSA-9706304 (Reactome)
Active FLT3R-HSA-9706308 (Reactome)
Active FLT3R-HSA-9706312 (Reactome)
Active FLT3R-HSA-9706315 (Reactome)
Active FLT3R-HSA-9706319 (Reactome)
Active FLT3R-HSA-9706323 (Reactome)
Active FLT3R-HSA-9706328 (Reactome)
Active FLT3R-HSA-9706330 (Reactome)
Active FLT3R-HSA-9706336 (Reactome)
Active FLT3R-HSA-9706354 (Reactome)
Active FLT3mim-catalysisR-HSA-9699578 (Reactome)
BCL2L1 gene:PTPN11:p-STAT5ArrowR-HSA-9698021 (Reactome)
BCL2L1 gene:PTPN11:p-STAT5ArrowR-HSA-9698026 (Reactome)
BCL2L1 geneR-HSA-9698021 (Reactome)
BCL2L1 geneR-HSA-9698026 (Reactome)
BCL2L11 geneR-HSA-9699574 (Reactome)
BCL2L11ArrowR-HSA-9699574 (Reactome)
BCL2L1ArrowR-HSA-9698026 (Reactome)
CBLR-HSA-9706293 (Reactome)
CDKN1A geneR-HSA-9698041 (Reactome)
CDKN1A geneR-HSA-9698043 (Reactome)
CDKN1AArrowR-HSA-9698043 (Reactome)
CDKN1B geneR-HSA-9699575 (Reactome)
CDKN1BArrowR-HSA-9699575 (Reactome)
CDKN1BR-HSA-9699578 (Reactome)
CSKR-HSA-9706298 (Reactome)
FLT3 E3 ubiquitin ligasesmim-catalysisR-HSA-9706354 (Reactome)
FLT3 extracellular

domain, kinase domain and juxtamembrane domain mutant

dimers		ArrowR-HSA-9695838 (Reactome)
FLT3 extracellular

domain, kinase domain and juxtamembrane domain mutant

dimers		R-HSA-9695834 (Reactome)
FLT3 extracellular

domain, kinase domain and juxtamembrane domain mutant

dimers		mim-catalysisR-HSA-9695834 (Reactome)
FLT3 extracellular

domain, kinase domain and juxtamembrane

domain mutants		R-HSA-9695838 (Reactome)
FLT3 fusion dimersArrowR-HSA-9703433 (Reactome)
FLT3 fusion dimersR-HSA-9703437 (Reactome)
FLT3 fusion dimersmim-catalysisR-HSA-9703437 (Reactome)
FLT3 fusion proteinsR-HSA-9703433 (Reactome)
FLT3:FLT3-binding type II TKIsArrowR-HSA-9695831 (Reactome)
FLT3:FLT3-binding type II TKIsTBarR-HSA-9604767 (Reactome)
FLT3LG dimer:FLT3:FLT3-binding type I TKIsArrowR-HSA-9695828 (Reactome)
FLT3LG dimer:FLT3:FLT3-binding type I TKIsTBarR-HSA-9604767 (Reactome)
FLT3LG dimer:FLT3 dimerArrowR-HSA-8854736 (Reactome)
FLT3LG dimer:FLT3 dimerR-HSA-9604767 (Reactome)
FLT3LG dimer:FLT3 dimermim-catalysisR-HSA-9604767 (Reactome)
FLT3LG dimer:FLT3ArrowR-HSA-6786789 (Reactome)
FLT3LG dimer:FLT3R-HSA-8854736 (Reactome)
FLT3LG dimer:FLT3R-HSA-9695828 (Reactome)
FLT3LG dimerR-HSA-6786789 (Reactome)
FLT3R-HSA-6786789 (Reactome)
FLT3R-HSA-8854736 (Reactome)
FLT3R-HSA-9695831 (Reactome)
FOXO3ArrowR-HSA-9699574 (Reactome)
FOXO3ArrowR-HSA-9699575 (Reactome)
FOXO3R-HSA-9699579 (Reactome)
FYNR-HSA-9605259 (Reactome)
GAB2R-HSA-9606624 (Reactome)
GAB2R-HSA-9703440 (Reactome)
GDPArrowR-HSA-9607304 (Reactome)
GDPArrowR-HSA-9703441 (Reactome)
GRAP2R-HSA-9706304 (Reactome)
GRB10R-HSA-9706308 (Reactome)
GRB2-1R-HSA-9604738 (Reactome)
GRB2-1R-HSA-9703442 (Reactome)
GTPR-HSA-9607304 (Reactome)
GTPR-HSA-9703441 (Reactome)
H+R-HSA-9698758 (Reactome)
H2O2ArrowR-HSA-9698758 (Reactome)
H2O2TBarR-HSA-9698408 (Reactome)
H2OR-HSA-9698408 (Reactome)
HCKR-HSA-9609274 (Reactome)
LCKR-HSA-9706312 (Reactome)
NADP+ArrowR-HSA-9698758 (Reactome)
NADPHR-HSA-9698758 (Reactome)
NOX4 gene:p-STAT5ArrowR-HSA-9698754 (Reactome)
NOX4 gene:p-STAT5ArrowR-HSA-9698762 (Reactome)
NOX4 geneR-HSA-9698754 (Reactome)
NOX4 geneR-HSA-9698762 (Reactome)
NOX4ArrowR-HSA-9698762 (Reactome)
NOX4mim-catalysisR-HSA-9698758 (Reactome)
O2R-HSA-9698758 (Reactome)
PIK3CAR-HSA-9698170 (Reactome)
PIK3CAR-HSA-9703434 (Reactome)
PIK3CAR-HSA-9706345 (Reactome)
PIK3R1R-HSA-9607224 (Reactome)
PIK3R1R-HSA-9703439 (Reactome)
PIK3R1R-HSA-9706340 (Reactome)
PIM1 geneR-HSA-9703436 (Reactome)
PIM1ArrowR-HSA-9703436 (Reactome)
PTPN11:p-STAT5ArrowR-HSA-9698013 (Reactome)
PTPN11:p-STAT5ArrowR-HSA-9698016 (Reactome)
PTPN11:p-STAT5R-HSA-9698016 (Reactome)
PTPN11:p-STAT5R-HSA-9698021 (Reactome)
PTPN11R-HSA-9604969 (Reactome)
PTPN11R-HSA-9606784 (Reactome)
PTPRJmim-catalysisR-HSA-9698408 (Reactome)
PiArrowR-HSA-9698408 (Reactome)
R-HSA-6786789 (Reactome) FLT3 is a member of the Class III Receptor Tyrosine Kinase Family, which also includes CSF1R, KIT, PDGFRA and PDGFRB. It binds the cytokine FLT3LG (Hannum et al. 1994), which regulates differentiation, proliferation and survival of hematopoietic progenitor cells and dendritic cells.

FLT3LG is probably dimeric. Binding to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012), which promotes phosphorylation of the tyrosine kinase domain, activating the receptor and consequently the downstream effectors. Early studies of FLT3 using a chimeric receptor composed of the extracellular domain of human FMS and the transmembrane and cytoplasmic domains of FLT3 demonstrated the activation of PLCG1, RASA1, SHC, GRB2, VAV, FYN, and SRC pathways. PLCG1, SHC, GRB2, and FYN were found to directly associate with the cytoplasmic domain of FLT3 (Dosil et al. 1993). Later studes using the full-length human receptor identified that FLT3LG binding to FLT3 leads to FLT3 autophosphorylation, association of FLT3 with GRB2, tyrosine phosphorylation of SHC and CBL, formation of a complex that includes CBL, the p85 subunit of PI3K and GAB2, and tyrosine phosphorylation of GAB1 and GAB2 and their association with PTPN11 (SHP-2) and GRB2 (Zhang and Broxmeyer, 2000). PTPN11 (SHP-2), but not PTPN6 (SHP-1) binds GRB2 directly and becomes tyrosine-phosphorylated in response to FLT3LG stimulation. INPP5D (SHIP) also becomes tyrosine-phosphorylated after FLT3LG stimulation but binds to SHC. GAB1 and GAB2 are rapidly tyrosine phosphorylated after FLT3LG stimulation of cells, interacting with tyrosine-phosphorylated PTPN11, p85 subunit of PI3K, GRB2, and SHC (Zhang & Broxmeyer 2000). GAB may mediate the downstream activation of PTPN11, PI3K and thereby PDK1 and AKT which activate the mTOR pathway (Grafone et al. 2012), and possibly the RAS/RAF/MAPK pathway. (Zhang et al. 1999, Marchetto et al. 1999, Zhang e& Broxmeyer 2000). Activation of FLT3 leads to limited activation of STAT5A via a JAK-independent mechanism (Zhang et al. 2000).

FLT3 is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3 (Small 2006).
R-HSA-8854736 (Reactome) Binding of FLT3LG to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012).
R-HSA-9604738 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2) and facilitate downstream regulation of effectors (Masson et al. 2009, Chonabayashi et al. 2013). Experiments confirming this event were performed in mouse cells.
R-HSA-9604767 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in FLT3 receptor, which facilitates its dimerization. This process exposes phosphate acceptor sites in the catalytic domain of FLT3. Subsequently, FLT3 autophosphorylates at these sites. Several phosphorylation sites have been reported and there may be more modifications required to fully activate FLT3 (Heiss et al. 2006, Masson et al. 2009, Razumovskaya et al. 2009). Experiments confirming this event were performed in mouse cells.
R-HSA-9604969 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, tyrosine-protein phosphatase non-receptor type 11 (PTPN11) has been reported to directly bind to the Y599 site of Flt3 receptors thereby facilitating downstream regulation of effectors (Heiss et al. 2006, Nabinger et al. 2013). Experiments confirming this event were performed in mouse cells. Interaction of FLT3 with PTPN11 is known to trigger STAT5 activation in various pathological conditions (Mizuki M et al. 2000, Rocnik JL et al. 2006).
R-HSA-9605259 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Subsequently, tyrosine-protein kinase Fyn (FYN) associates with the phosphorylated residues of fully active FLT3 (Y591, Y599 and pY955) through its SH2 domain (Dosil et al. 1993, Chougule et al. 2016). Experiments confirming this event were performed in mouse cells.
R-HSA-9606622 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits GRB2-associated-binding protein 2 (GAB2). Consequently, GAB2 is phosphorylated (Zhang et al. 2000, Masson et al. 2009, Chonabayashi et al. 2013). The precise phosphorylation mechanism of GAB2 is unclear. Experiments confirming this event were performed in mouse cells.
R-HSA-9606624 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2). Subsequently, GRB2-associated-binding protein 2 (GAB2) binds GRB2 (Zhang et al. 2000, Masson et al. 2009, Chonabayashi et al. 2013). Experiments confirming this event were performed in mouse cells.
R-HSA-9606784 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits GRB2-associated-binding protein 2 (GAB2). Consequently, GAB2 is phosphorylated and recruits tyrosine-protein phosphatase non-receptor type 11 (PTPN11). The serine residue at position 623 in GAB2 is known to be involved in PTPN11 binding (Zhang et al. 2000, Arnaud et al. 2004). The precise association mechanism of GAB2 and PTPN11 is unclear. Experiments confirming this event were performed in mouse cells. Interaction of FLT3 with PTPN11 is known to trigger STAT5 activation in various pathological conditions.
R-HSA-9607224 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits GRB2-associated-binding protein 2 (GAB2). Consequently, GAB2 is phosphorylated and recruits phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1). The p85 alpha subunit of PIK3R1 is known to bind with GAB2. Ultimately, the PI3K/AKT pathway is activated (Zhang et al. 2000, Masson et al. 2009). Experiments confirming this event were performed in mouse cells.
R-HSA-9607301 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits Son of sevenless homolog 1 (SOS1). Consequently, this triggers the activation of the ERK signaling cascade (Li et al. 1993).
R-HSA-9607304 (Reactome) Son of sevenless homolog 1 (SOS1) is the guanine nucleotide exchange factor (GEF) for rat sarcoma (RAS) protein. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP).
R-HSA-9609274 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Tyrosine-protein kinase HCK (HCK) associates with the phosphorylated Y589 and Y591 residues of FLT3. This binding results in further phosphorylation of the FLT3 receptor to make it fully active (Heiss et al. 2006, Mitina et al. 2007). There may be more unknown binding sites for HCK on FLT3.
R-HSA-9695828 (Reactome) FLT3 can be bound and inhibited by class I tyrosine kinase inhibitors including sunitinib, lesaurtinib, crenolanib, gilteritinib and midostaurin, among others. Type I inhibitors bind in the ATP-binding site of the active conformation and prevent activation of the kinase (reviewed in Larrosa-Garcia and Baer, 2017; Lim et al, 2017; Klug et al, 2018).
R-HSA-9695831 (Reactome) FLT3 can be bound and inhibited by class II tyrosine kinase inhibitors including sunitinib, sorafenib and others. Type II inhibitors bind to the inactive conformation of the kinase and prevent its activation (reviewed in Larrosa-Garcia and Baer, 2017; Lim et al, 2017; Klug et al, 2018).
R-HSA-9695834 (Reactome) Activating mutations in the juxtamembrane, kinase and extracellular regions of FLT3 lead to ligand-independent dimerization, trans-autophosphorylation and constitutive downstream signaling (Kiyoi et al, 1998; Yamamoto et al, 2001; Clark et al, 2004; Zheng et al, 2004; Stirewalt et al, 2004; Jiang et al, 2004; Schittenhelm et al, 2006; Reindl et al, 2006; Frohling et al, 2007; Breteinbeucher et al, 2009; Huang et al, 2016; reviewed in Klug et al, 2018; Staudt et al, 2018; Daver et al, 2019).
R-HSA-9695838 (Reactome) Mutations in FLT3 are common in acute myeloid leukemia, with internal tandem duplications in the juxtamembrane or kinase domain occurring in 25% of FLT3-positive AMLs, and missense mutations in the kinase domain occurring in 7-10% of cases (reviewed in Klug et al, 2018; Daver et al, 2019; Staudt et al, 2018). Mutant receptors support ligand-independent dimerization and result in constitutive activation and signaling (Kiyoi et al, 1998; Yamamoto et al, 2001; Clark et al, 2004; Zheng et al, 2004; Stirewalt et al, 2004; Jiang et al, 2004; Brandts et al, 2005; Schittenhelm et al, 2006; Reindl et al, 2006; Frohling et al, 2007; Breteinbeucher et al, 2009; Huang et al, 2016; reviewed in Klug et al, 2018; Staudt et al, 2018; Daver et al, 2019).
R-HSA-9698005 (Reactome) STAT5 is phosphorylated downstream of FLT3 ITD mutants (Hayakawa et al, 2000; Mizuki et al, 2000; Spiekermann et al, 2003, Rocnik et al, 2006). Recombinant FLT3 ITD is able to directly phosphorylate STAT5 in vitro, but phosphorylation may also be mediated by SRC family kinases in vivo (Choudhary et al, 2007; Leischner et al, 2012; Voisset et al, 2010; reviewed in Kazi and Ronnstrand, 2019 a, b). FLT3-dependent STAT5 activation contributes to the expression of a number of genes involved in proliferation and transformation (Mizuki et al 2003; Takahashi et al, 2004; Kim et al, 2005; Nabinger et al, 2013; Bertoli et al, 2015; reviewed in Kazi and Ronnstrand, 2019 a).
R-HSA-9698007 (Reactome) PTPN11 and FLT3 Y599 are required for the recruitment and activation of the STAT5 signaling pathway. STAT5 signaling appears to be more active in FLT3 mutant proteins, particularly FLT3 alleles bearing internal tandem duplications, than it is in wild-type signaling (Hayakawa et al, 2000; Mizuki et al, 2000; Takahashi et al, 2004; Spiekermann et al, 2003; Heiss et al, 2006; Nabinger et al, 2013; Richine et al, 2016; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9698013 (Reactome) In the case of FLT3-ITD-dependent BCL2L1 expression, it has been demonstrated that PTPN11 and STAT5 colocalize at the STAT5 binding sites in the promoter, suggesting that this complex dissociates from the receptor and translocates to the nucleus as a unit (Nabinger et al, 2013).
R-HSA-9698016 (Reactome) PTPN11:p-STAT5 has been shown to bind to gamma-interferon activation sites (GAS) in the promoter of BCL2L1 downstream of FLT3-ITD signaling, suggesting that this complex translocates from the cytosol to the nucleus (Nabinger et al, 2013; reviewed in Murphy and Rani, 2015).
R-HSA-9698021 (Reactome) PTPN11:STAT5 binds to gamma interferon activation sites (GAS) in the promoter of the BCL2L1 gene as assessed by ChIP and reporter gene assays. PTPN11 and STAT5 promote hyperproliferation and transformation in a FLT3-ITD phospho-Y599-dependent manner (Nabinger et al, 2013: Heiss et al, 2006).
R-HSA-9698026 (Reactome) FLT3-ITD mutant cells express BCL2L1 in a STAT5 and PTPN11-dependent manner, contributing to hyperproliferation and survival (Nabinger et al, 2013).
R-HSA-9698029 (Reactome) Phosphorylated STAT5 is released from the receptor to fill its role as a nuclear transcription factor (Mizuki et al, 2003; Takahashi et al, 2004; Kim et al, 2005; Nabinger et al, 2013; reviewed in Murphy and Rani, 2015).
R-HSA-9698033 (Reactome) Phosphorylated STAT5 translocates to the nucleus where it promotes transcription of a number of FLT3-dependent promoters (Mizuki et al, 2003; Takahashi et al, 2004; Kim et al, 2005; Nabinger et al, 2013; reviewed in Kazi and Ronnstrand, 2019; Rani and Murphy, 2015). STAT5-dependent transcriptional regulation of downstream targets contributes to hyperproliferation and oncogenesis in a number of cancers (reviewed in Rani and Murphy, 2015).
R-HSA-9698041 (Reactome) p-STAT5 binds to its cognate sites in the promoter of the CDKN1A gene in a FLT3-ITD-dependent manner as assessed by reporter assay and electrophoretic mobility shift assay (EMSA) (Takahashi et al, 2004).
R-HSA-9698043 (Reactome) STAT5 binding to its cognate sites at positions -692 and -684 of the CDKN1a promoter leads to FLT3-dependent CDKN1A expression (Takahashi et al, 2004).
R-HSA-9698170 (Reactome) The 110 kDa catalytic subunit of PI3K is recruited to the activated FLT3 receptor through interaction with the p85 regulatory subunit. GAB2-mediated conformational changes in the p85 regulatory subunit stimulate interaction with p110, and promote PI3K/AKT signaling downstream of the activated FLT3 receptor (Zhang et al, 1999; Zhang et al, 2000; Masson et al, 2009; Mandelker et al, 2009; Burke et al, 2011; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9698408 (Reactome) The protein tyrosine phosphatase PTPRJ (also known as DEP1) dephosphorylates active FLT3 on juxtamembrane tyrosine residues Y589, Y591 and Y599 and Y955 and on kinase domain tyrosine residues Y842 (not shown) and Y955. Dephosphorylation negative regulates FLT3-dependent signaling, particularly through the ERK and PLCgamma pathways, with moderate effects on STAT signaling and minor effects on signaling through AKT (Arora et al, 2011). Dephosphorylation is effected through a direct interaction between the phosphatase and the active receptor. Depletion of PTPRJ by shRNA caused proliferation and colony formation of the mouse myeloid cell line 32D in the presence of ligand but did not promote myeloid disease development (Arora et al, 2011). FLT3 ITD mutants also directly interact with PTPRJ, but autophosphorylation of the mutant receptors is not affected by PTPRJ depletion (Arora et al, 2011). FLT3 ITD insensitivity to PTPTJ-mediated dephosphorylation is the result of increased reactive oxygen (ROS) levels in FLT3 mutants cells, which inactivate the catalytic activity of PTPRJ (Sallmyr et al, 2008; Reddy et al, 2011; Godfrey et al, 2012; Kresinsky et al, 2015; Jayavelu et al, 2016; reviewed in Jayavelu et al, 2016).
R-HSA-9698754 (Reactome) Tyrosine phosphorylated STAT5 binds to target interferon gamma activated sequence (GAS) elements in the promoters of the NOX4 gene in response to signaling by FLT3 ITD mutants. NOX4 expression increases the production of reactive oxygen species, causing the oxidative inactivation of the protein phosphatase PTPRJ (also known as DEP1). As a result, FTL3 ITD mutants exhibit increased signaling, proliferation and transformation relative to WT FLT3 cells (Jayavelu et al 2016a; Godfrey et al, 2012; Kresinsky et al, 2015; reviewed in Jayavelu et al, 2016b).
R-HSA-9698758 (Reactome) NOX4 catalyzes the synthesis of H2O2 downstream of FLT3 ITD mutants in a STAT5-dependent manner, increasing the levels of reactive oxygen species (ROS) (Jayvavelu et al, 2016a; Sallmyer et al, 2008; Reddy et al, 2011). High ROS levels cause oxidative inactivation of the protein tyrosine phosphatase PTPRJ, also known as DEP1, a negative regulator of FLT3 signaling. In consequence, FLT3 ITD-expressing cells have higher signaling activity than the wild type, as well as increased proliferation (Arora et al, 2011; Godfrey et al, 2012; Kresinsky et al, 2015; Jayavelu et al, 2016a; reviewed in Jayavelu et al, 2016b).
R-HSA-9698762 (Reactome) NOX4 expression is upregulated in a FLT3 ITD- and STAT5-dependent manner relative to levels in wild type cells. NOX4 expression increases production of reactive oxygen species, resulting in the inhibition of the catalytic site of the FLT3 negative regulator PTPRJ (also known as DEP1). As a consequence, FLT3 ITD mutants show enhance signaling, proliferation and colony forming ability (Arora et al, 2011; Godfrey et al, 2012; Kesinsky et al, 2015; Jayavelu et al, 2016; reviewed in Jayavelu et al, 2016).
R-HSA-9699574 (Reactome) BCL2L11 (also known as BIM) is a pro-apoptotic factor whose expression is downregulated by FLT3 signaling as a consequence of AKT-dependent FOXO3 phosphorylation and nuclear export (Brandts et al, 2005; Scheijen et al, 2004; reviewed in Kazi and Ronnstrand, 2019; Yadav et al, 2018).. Downregulation of BCL2L11 may contribute to evasion of apoptosis and promote cellular survival downstream of FLT3 and FLT3 ITD signaling (Nordigarden et al, 2009).
R-HSA-9699575 (Reactome) The promoter of the CDKN1B gene, encoding CDK inhibitor p27Kip1, contains forkhead box elements that are required for induction of CDKN1B gene transcription by FOXO transcription factors FOXO1, FOXO3 (Dijkers et al, 2000, Lees et al, 2008) and FOXO4 (Medema et al, 2000). Direct binding of FOXO transcription factors to the CDKN1B gene promoter has not been demonstrated.
CDKN1B expression is downregulated by FLT3- and FLT3-ITD signaling as a consequence of AKT-dependent FOXO3 phosphorylation and nuclear export. Downregulation of CDKN1B may contribute to cellular proliferation downstream of FLT3 signaling (Brandts et al, 2005; Scheijen et al, 2004; reviewed in Kazi and Ronnstrand, 2019; Yadav et al, 2018). Active FLT3 may also promote cell cycle progression by directly phopshorylating and inhibiting CDKN1B (Peschel et al, 2017).
R-HSA-9699578 (Reactome) Active FLT3 binds to the cyclin dependent kinase inihibitor CDKN1B (also known as p27 KIP1) and phosphorylates it at tyrosine 88. (Peschel et al, 2017). Phosphorylation at Y88 dislodges the 3-10 helix of CDKN1B from the active site of CDK2 or CDK4, thus paritally relieving CDKN1B-dependent inhibition (Grimmler et al. 2007, Ray et al. 2009). This enables CDK2 (and possibly CDK4) to phosphorylate CDKN1B on threonine residue T187, which is a prerequisite for ubiquitin-mediated degradation of CDKN1B (Montagnoli et al. 1999, Grimmler et al. 2007).
R-HSA-9699579 (Reactome) AKT phosphorylation of the pro-apoptotic Forkhead transcription factor FOXO3 and other Foxo family members occurs downstream of FLT3 and FLT3-ITD-mediated signaling (Scheijen et al, 2004; Brandts et al 2005; reviewed in Kazi and Roonstrand, 2019). AKT-mediated phosphorylation promotes nuclear export, resulting in a decrease in expression of apoptosis-promoting FOXO3-target genes (Brunet et al, 1999; reviewed in Burgering, 2008; Yadav et al, 2018).
R-HSA-9699581 (Reactome) AKT-mediated phosphorylation of FOXO3 downstream of FLT3 and FLT3-ITD signaling promotes its inactivation and translocation to the cytosol, interfering with its pro-apoptotic transcription factor activity as assessed by protein and RNA levels of BCL2L11/BIM and CDKN1B/p27 KIP (Scheijen et al, 2004; reviewed in Burgering, 2008; Yadav et al, 2018; Kazi and Ronnstrand, 2019)
R-HSA-9703430 (Reactome) Activated FTL3 fusion mutants have been shown to signal through the MAP kinase pathway as assessed through increased levels of phosphorylated ERK/MAPK proteins (Grand et al, 2007; Vu et al, 2009; Troadec et al, 2017; Chonabayashi et al, 2013; reviewed in Kazi and Roonstrand, 2019). The RAS guanine nucleotide exchange factor (GEF) SOS1 is presumed to be recruited downstream of GRB2 binding to FLT3 fusion protein, but this has not been directly demonstrated.
R-HSA-9703432 (Reactome) Phosphorylated STAT5 is released from the receptor to fulfill its role as a nuclear transcription factor (Grand et al, 2007; Vu et al, 2009; Chonabayshi et al, 2013; reviewed in Murphy and Rani, 2015; Kazi and Roonstrand, 2019).
R-HSA-9703433 (Reactome) In addition to internal tandem duplications and activating point mutations, the FLT3 locus is also subject at low frequency to translocations (reviewed in Reiter and Gotlib, 2017; Kazi and Roonstrand, 2019). These translocations generally bring together an N-terminal partner gene encoding a dimerization domain with the intracellular portion of FLT3 containing the kinase domain and result in a protein that undergoes constitutive, ligand-independent dimerization. To date, 6 fusion partner genes have been identified: ETV6 (the most frequent), GOLGB1, SPTBN1, ZMYM2, TRIP11 and MYO18A, although not all have been functionally characterized. Where examined, the fusion proteins promote downstream signaling through the PI3K/AKT, MAP kinase and STAT5 signaling pathways and support IL-3-independent transformation of murine BaF3 cells (Baldwin et al, 2007; Vu et al, 2006; Vu et al, 2009; Walz et al, 2011; Falchi et al, 2014; Chung et al, 2017; Troadec et al, 2017; Grand et al, 2007; Jawhar et al, 2017; Zhang et al, 2018; Chonabayashi et al, 2013; reviewed in Kazi and Roonstrand, 2019).
R-HSA-9703434 (Reactome) The 110 kDa catalytic subunit of PI3K is likely recruited to FLT3 fusions through interaction with the p85 regulatory subunit, as is the case for the wild-type receptor. GAB2-mediated conformational changes in the p85 regulatory subunit stimulate interaction with p110, and promote PI3K/AKT signaling downstream of activated FLT3 (Zhang et al, 1999; Zhang et al, 2000; Vu et al, 2007; Masson et al, 2009; Grand et al, 2007; Troadec et al, 2017; Chonabayashi et al, 2013; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9703435 (Reactome) Active FLT3 fusions promote signaling through the STAT5 pathway as assessed by Western blotting against phosphorylated STAT5 (Grand et al, 2007; Vu et al, 2009; Chonabayashi et al, 2013; reviewed in Kazi and Roonstrand, 2019). In studies with the ETV6-FLT3 fusion EF1, STAT5 activation was shown to depend on tyrosine residues in the juxtamembrane domain and tyrosine kinase domain 1 region of FLT3 (Vu et al, 2009).
R-HSA-9703436 (Reactome) PIM1 is a serine threonine kinase with roles in cellular proliferation, survival and escape from apoptosis. Its expression is upregulated in a number of hematological cancers (reviewed in Arrouchi et al, 2019; Zhang et al, 2018). PIM1 expression is upregulated in BaF3 cells expressing constitutively activated STAT5, and STAT5-mediated upregulation of PIM1 has been shown downstream of FLT ITD and ETV6-FLT3 fusion mutants (Nosaka et al, 1999; Kim et al, 2005; Vu et al, 2009; Okada et al, 2018).
R-HSA-9703437 (Reactome) After ligand-independent dimerization, FLT3 fusion proteins are trans-autophosophorylated on tyrosine residues, activating downstream signaling through PI3K/AKT, MAP kinase and STAT5 pathways (Vu et al, 2006; Grand et al, 2007; Vu et al, 2009; Troadec et al, 2017; Chonabayashi et al, 2013; reviewed in Kazi and Roonstrand, 2019).
R-HSA-9703438 (Reactome) GAB2 is presumed to be phosphorylated downstream of active FLT3 fusion proteins, but this has not been directly demonstrated. ETV6-FLT3 is unable to transform primary myeloid cells from the bone marrow of Gab2-/- mice, implicating signaling through this pathway (Chonabayashi et al, 2013).
R-HSA-9703439 (Reactome) FLT3 fusions signal through the PI3K/AKT pathway as assessed by increased phosphorylation of AKT downstream of activated fusions (Grand et al, 2007; Vu et al, 2009; Troadec et al, 20017; Chonabayashi et al, 2013; reviewed in Kazi and Roonstrand, 2019). Recruitment and activation of PI3K is likely mediated by GRB2-GAB2 as is the case for the wild-type receptor, although this has not been directly demonstrated (Zhang et al, 1999; Zhang et al, 2000; Masson et al, 2009).
R-HSA-9703440 (Reactome) The transforming ability of ETV6-FLT3 fusion proteins is reduced in a GAB2 null background, implicating signaling through this GRB2-interactor as critical for the oncogenic program driven by the fusions (Chonabayashi et al, 2013).
R-HSA-9703441 (Reactome) SOS1-mediated nucleotide exchange on RAS is presumed to occur downstream of activated FLT3 fusion mutants, leading to increased phosphorylation of MAPK/ERK proteins (Grand et al, 2007; Vu et al, 2009; Troadec et al, 2017; Chonabayashi et al, 2013; reviewed in Kazi and Roonstrand et al, 2019).
R-HSA-9703442 (Reactome) FLT3 fusion proteins may signal through the PI3K/AKT and MAP kinase signaling pathway by first recruiting GRB2 to the phosphorylated receptor. This has been directly demonstrated for one of the ETV6-FLT3 fusions, where GRB2 binding was shown to depend on tyrosine residues corresponding to Y314 and Y354 of the ETV6 portion and Y768, Y955 and Y969 of the FLT3 portion. Mutation of these residues to phenylalanies abrogates GRB2 binding and interferes with downstream signaling and the ability of the fusion protein to transform BaF3 cells to IL-3-independent growth (Chonabayashi et al, 2013).
R-HSA-9706287 (Reactome) The Abelson (ABL) family of non-receptor tyrosine kinase 2 (ABL2, also known as ARG) binds to tyrosine phosphorylated FLT3. ABL2 binding inhibits FLT3-dependent AKT signaling without affecting other downstream pathways like the MAP kinase and STAT cascades, and without affecting FLT3 phosphorylation or stability. The mechanism for ABL2-mediated negative regulation of FLT3 AKT signaling remains to be elucidated (Kazi et al, 2017; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706293 (Reactome) Active FLT3 is bound by the E3 ubiquitin protein ligase CBL. In addition to direct interaction with the FLT3 receptor, CBL may also interact indirectly through GRB2. CBL interacts with the receptor in a FL ligand-dependent way, and mutation of FLT3 tyrosine residues Y589 and Y599 abrogates FLT3-dependent CBL phosphorylation (Sargin et al, 2007; Reindl et al, 2009; Heiss et al, 2006). FLT3-mediated phosphorylation of CBL promotes receptor ubiquitination and internalization, consistent with what is observed with other Type III receptor tyrosine kinases (reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706298 (Reactome) The COOH-terminal SRC kinase (CSK) interacts with FLT3 in a phosphorylation-dependent manner through the SH2 domain of CSK. Interaction with CSK downregulates FLT3-dependent signaling through the AKT and MAP kinase pathway without affecting receptor ubiquitination or stability. Consistent with this, siRNA depletion of CSK increased GAB2 and PTPN11 phosphorylation (Kazi et al, 2013; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706304 (Reactome) GRB2-related adaptor protein 2 (GRAP2, also known as GADS) binds to active FLT3 through Y955 and Y969, overlapping with the FLT3 binding site of GRB2. GRAP2-binding stimulates FLT3 signaling through the AKT, MAP kinase, STAT and p38 pathways. Expression of GRAP2 promotes proliferation and colony formation in cell lines and tumor formation in a mouse xenograft model (Chougule et al, 2016; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706308 (Reactome) Growth factor receptor-bound protein 10 (GRB10) can serve as an adaptor linking FLT3 to the p85 subunit of PI3 kinase, and thereby lead to activation of AKT signaling (Kazi and Ronnstrand, 2013; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706312 (Reactome) SRC family of non-receptor tyrosine kinase LCK binds to tyrosine-phosphorylated FLT3. LCK-binding stimulates STAT signaling downstream of FLT3-ITD mutants and promotes cellular proliferation and tumor formation in mouse models (Marhall et al, 2017).
R-HSA-9706315 (Reactome) SH2B3 (also called LNK) is an adaptor protein that binds to tyrosine phosphorylated FLT3 through at least 3 tyrosine residues, Y572, Y591 and Y919 (Lin et al, 2012). SH3B2 is a known CBL interactor, so may contribute to FLT3 downregulation by promoting the CBL-dependent ubiquitination and internalization of the receptor, although this hasn't been formally demonstrated (Lv et al, 2017; Lin et al, 2012; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706319 (Reactome) SRC-like adaptor protein (SLA, also known as SLAP) binds to tyrosine phosphorylated FLT3 (Kazi and Ronnstrand, 2012). This binding stimulates CBL-dependent FLT3 ubiquitination and internalization. Because SLAP is also known to bind to CBL, SLAP may function as an adaptor protein, bringing CBL to the FLT3 receptor. Direct interaction of CBL and SLAP has not be explicitly demonstrated in the context of FLT3 signaling, however (Dragone et al, 2006; Kazi et al, 2012, reviewed in Kazi and Ronnstrand, 2019). In addition to promoting the internalization of FLT3, SLAP also contributes to downstream signaling through the AKT, MAP kinase and p38 cascades. These roles are not shown in this pathway, however (Kazi et al, 2012).
R-HSA-9706323 (Reactome) SRC-like adaptor protein 2 (SLA2, also known as SLAP2) binds to tyrosine-phosphorylated FLT3 mainly through Y589 and Y591. Binding of SLA2 inhibits downstream signaling through AKT, MAP kinase and the p38 cascades and promotes receptor ubiquitination and internalization (Moharram et al, 2012). Because SLA2 is a known interactor of CBL, it is possible SLA2 indirectly recruits CBL to FLT3 to promote its downregulation, although this has not been explicitly demonstrated (Loreto et al, 2002; Moharram et al, 2012; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706328 (Reactome) The E3 ubiquitin ligase SOCS2 binds to tyrosine phosphorylated FLT3 through Y589 and Y919. SOCS2 contributes to ubiquitination, internalization and downregulation of active FLT3, consistent with known roles for SOCS family members (Kazi and Ronnstrand, 2013; reviewed in Kazi et al, 2014).
R-HSA-9706330 (Reactome) The E3 ubiquitin ligase SOCS6 binds to tyrosine phosphorylated FLT3 through Y591 and Y919. SOCS6 contributes to the ubiquitination and degradation of the active FLT3 receptor (Kazi et al, 2012; reviewed in Kazi et al, 2014).
R-HSA-9706336 (Reactome) Spleen-associated tyrosine kinase (SYK) binds to active FLT3 and transactivates it (Puissant et al, 2014).
R-HSA-9706340 (Reactome) GRB10 interacts directly with the p85 subunit of PI3 kinase downstream of active FLT3 (Kazi and Ronnstrand, 2013).
R-HSA-9706344 (Reactome) GRB10 is phosphorylated in response to treatment of cells with FL (Kazi and Ronnstrand, 2013).
R-HSA-9706345 (Reactome) GRB10 promotes signaling through the AKT pathway downstream of active FLT3. GRB10 is recruited to the active receptor by binding to phosphorylated tyrosine residues 572 and 793. Once bound, GRB10 recruits PI3K by direct interaction with the p85 regulatory subunit and subsequent recruitment of catalytic subunit (Kazi and Ronnstrand, 2013; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706350 (Reactome) FLT3 activation leads to tyrosine phosphorylation of CBL (Sargin et al, 2007; Reindl et al, 2009). Phosphorylation of CBL is abolished in FLT3 Y589 and Y599 mutants (Heiss et al, 2006).
R-HSA-9706354 (Reactome) FLT3 activity is negatively regulated by ubiquitin-mediated internalization (Sargin et al, 2007; Reindl et al, 2009; reviewed in Kazi and Ronnstrand, 2019). Several E3 ubiquitin ligases are implicated in the downregulation of active FLT3 including CBL, SOCS2 and SOCS6 (Sargin et al, 2007, Reindl et al, 2009; Kazi and Ronnstrand, 2013; Kazi et al, 2012).
Ubiquitination of human FLT3 in COS-7 cells is abrogated by the expression of a dominant negative form of CBL, implicating CBL as a major E3 ubiquitin ligase for the FLT3 receptor (Sargin et al, 2007). While direct ubiquitination of FLT3 by SOCS2 and SOCS6 has not been demonstrated, overexpression of these E3 ligases induces FLT3 ubiquitination and internalization in cell lines (Kazi and Ronnstrand, 2012; Kazi and Ronnstrand, 2013; reviewed in Kazi and Ronnstrand, 2019).
R-HSA-9706364 (Reactome) E3 ligase- mediated ubiquitination of FLT3 leads to its internalization to the endosomal compartment (Sargin et al, 2007; Reindl et al, 2009; reviewed in Kazi and Ronnstrand, 2019).
SH2B3R-HSA-9706315 (Reactome)
SLA2R-HSA-9706323 (Reactome)
SLAR-HSA-9706319 (Reactome)
SOCS2R-HSA-9706328 (Reactome)
SOCS6R-HSA-9706330 (Reactome)
SOS1R-HSA-9607301 (Reactome)
SOS1R-HSA-9703430 (Reactome)
STAT5R-HSA-9698007 (Reactome)
STAT5R-HSA-9703435 (Reactome)
SYKR-HSA-9706336 (Reactome)
Ub-pY FLT3:FLT3LG dimerArrowR-HSA-9706354 (Reactome)
Ub-pY FLT3:FLT3LG dimerArrowR-HSA-9706364 (Reactome)
Ub-pY FLT3:FLT3LG dimerR-HSA-9706364 (Reactome)
UbR-HSA-9706354 (Reactome)
active FLT3:ABL2ArrowR-HSA-9706287 (Reactome)
active FLT3:CBLArrowR-HSA-9706293 (Reactome)
active FLT3:CBLR-HSA-9706350 (Reactome)
active FLT3:CBLmim-catalysisR-HSA-9706350 (Reactome)
active FLT3:CSKArrowR-HSA-9706298 (Reactome)
active FLT3:GRAP2ArrowR-HSA-9706304 (Reactome)
active FLT3:GRB10ArrowR-HSA-9706308 (Reactome)
active FLT3:GRB10R-HSA-9706344 (Reactome)
active FLT3:GRB10mim-catalysisR-HSA-9706344 (Reactome)
active FLT3:LCKArrowR-HSA-9706312 (Reactome)
active FLT3:SH2B3ArrowR-HSA-9706293 (Reactome)
active FLT3:SH2B3ArrowR-HSA-9706315 (Reactome)
active FLT3:SLA2ArrowR-HSA-9706293 (Reactome)
active FLT3:SLA2ArrowR-HSA-9706323 (Reactome)
active FLT3:SLAArrowR-HSA-9706293 (Reactome)
active FLT3:SLAArrowR-HSA-9706319 (Reactome)
active FLT3:SOCS2ArrowR-HSA-9706328 (Reactome)
active FLT3:SOCS6ArrowR-HSA-9706330 (Reactome)
active FLT3:SYKArrowR-HSA-9706336 (Reactome)
active FLT3:p-Y GRB10:PI3KArrowR-HSA-9706345 (Reactome)
active FLT3:p-Y GRB10:PIK3R1ArrowR-HSA-9706340 (Reactome)
active FLT3:p-Y GRB10:PIK3R1R-HSA-9706345 (Reactome)
active FLT3:p-Y GRB10ArrowR-HSA-9706344 (Reactome)
active FLT3:p-Y GRB10R-HSA-9706340 (Reactome)
active FLT3:pY-CBLArrowR-HSA-9706350 (Reactome)
p-6Y FLT3

extracellular domain, kinase domain and juxtamembrane domain mutant

dimers		ArrowR-HSA-9695834 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:STAT5		ArrowR-HSA-9698007 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:STAT5		R-HSA-9698005 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:STAT5		mim-catalysisR-HSA-9698005 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:p-STAT5		ArrowR-HSA-9698005 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:p-STAT5		R-HSA-9698013 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11:p-STAT5		R-HSA-9698029 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11		ArrowR-HSA-9698029 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2:PTPN11		R-HSA-9698007 (Reactome)
p-6Y FLT3 ITD mutant

dimers:GRB2:p-Y

GAB2		ArrowR-HSA-9698013 (Reactome)
p-STAT5:CDKN1A geneArrowR-HSA-9698041 (Reactome)
p-STAT5:CDKN1A geneArrowR-HSA-9698043 (Reactome)
p-STAT5A, p-STAT5BArrowR-HSA-9698029 (Reactome)
p-STAT5A, p-STAT5BArrowR-HSA-9703432 (Reactome)
p-STAT5A, p-STAT5BR-HSA-9698033 (Reactome)
p-STAT5ArrowR-HSA-9698033 (Reactome)
p-STAT5ArrowR-HSA-9703436 (Reactome)
p-STAT5R-HSA-9698041 (Reactome)
p-STAT5R-HSA-9698754 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-9699579 (Reactome)
p-T32,S253,S315-FOXO3ArrowR-HSA-9699579 (Reactome)
p-T32,S253,S315-FOXO3ArrowR-HSA-9699581 (Reactome)
p-T32,S253,S315-FOXO3R-HSA-9699581 (Reactome)
p-Y FLT

fusions:GRB2:p-Y

GAB2:PI3KR1		ArrowR-HSA-9703439 (Reactome)
p-Y FLT

fusions:GRB2:p-Y

GAB2:PI3KR1		R-HSA-9703434 (Reactome)
p-Y FLT3 fusions:GRB2:GAB2ArrowR-HSA-9703440 (Reactome)
p-Y FLT3 fusions:GRB2:GAB2R-HSA-9703438 (Reactome)
p-Y FLT3 fusions:GRB2:GAB2mim-catalysisR-HSA-9703438 (Reactome)
p-Y FLT3 fusions:GRB2:SOS1ArrowR-HSA-9703430 (Reactome)
p-Y FLT3 fusions:GRB2:SOS1mim-catalysisR-HSA-9703441 (Reactome)
p-Y FLT3

fusions:GRB2:p-Y

GAB2:PI3K		ArrowR-HSA-9703434 (Reactome)
p-Y FLT3

fusions:GRB2:p-Y

GAB2		ArrowR-HSA-9703438 (Reactome)
p-Y FLT3

fusions:GRB2:p-Y

GAB2		R-HSA-9703439 (Reactome)
p-Y FLT3 fusions:p-STAT5ArrowR-HSA-9703435 (Reactome)
p-Y FLT3 fusions:p-STAT5R-HSA-9703432 (Reactome)
p-Y FLT3 fusion dimers:GRB2ArrowR-HSA-9703442 (Reactome)
p-Y FLT3 fusion dimers:GRB2R-HSA-9703430 (Reactome)
p-Y FLT3 fusion dimers:GRB2R-HSA-9703440 (Reactome)
p-Y FLT3 fusion dimersArrowR-HSA-9703437 (Reactome)
p-Y FLT3 fusion dimersR-HSA-9703435 (Reactome)
p-Y FLT3 fusion dimersR-HSA-9703442 (Reactome)
p-Y768,Y969 FLT3 dimer:FLT3LG dimerArrowR-HSA-9698408 (Reactome)
p-Y88-CDKN1BArrowR-HSA-9699578 (Reactome)
p21 RAS:GDPR-HSA-9607304 (Reactome)
p21 RAS:GDPR-HSA-9703441 (Reactome)
p21 RAS:GTPArrowR-HSA-9607304 (Reactome)
p21 RAS:GTPArrowR-HSA-9703441 (Reactome)
type I FLT3-binding TKIsR-HSA-9695828 (Reactome)
type II FLT3-binding TKIsR-HSA-9695831 (Reactome)
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