FLT3 signaling (Homo sapiens)

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141715, 23104, 2620, 232, 615, 20, 2313, 203215, 20, 2332, 19, 232, 5, 9, 16cytosolADPActive FLT3:HCKActiveFLT3:GRB2:p-Y-GAB2:PTPN11Autophosphorylated FLT3 PTPN11 ActiveFLT3:GRB2:GAB2S-Farn-Me KRAS4B FLT3LG dimer:FLT3dimerGAB2FLT3 FLT3LG dimerSTAT5 ActivationAutophosphorylated FLT3 p-Y-GAB2 p21 RAS:GTPFLT3LG S-Farn-Me-PalmS KRAS4A GRB2-1 Autophosphorylated FLT3 Autophosphorylated FLT3 p-Y-GAB2 p-Y-GAB2 GRB2-1Active FLT3:FYNSOS1 ActiveFLT3:GRB2:SOS1FLT3LG FLT3LG ATPGDP p21 RAS:GDPAutophosphorylated FLT3 FLT3ADPS-Farn-Me KRAS4B FYNSOS1S-Farn-Me PalmS NRAS FLT3LG FLT3LG GRB2-1 ATPActive FLT3: GRB2PTPN11 FYN FLT3LG S-Farn-Me-PalmS KRAS4A FLT3LG Autophosphorylated FLT3 GDPFLT3LG dimer:FLT3Autophosphorylated FLT3 ActiveFLT3:GRB2:p-Y-GAB2:PIK3R1FLT3LG FLT3LG PTPN11GTP FLT3LG GRB2-1 S-Farn-Me PalmS NRAS Active FLT3HCK PIK3R1ActiveFLT3:GRB2:p-Y-GAB2FLT3LG PIK3R1 Autophosphorylated FLT3 Autophosphorylated FLT3 GRB2-1 FLT3LG HCKGRB2-1 GAB2 RAF/MAP kinasecascadeAutophosphorylated FLT3 S-Farn-Me-2xPalmS HRAS FLT3 FLT3LG GTPS-Farn-Me-2xPalmS HRAS PI3K CascadeActive FLT3:PTPN11GRB2-1 1, 7, 8, 11, 12, 18...525


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.

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Pathway is converted from Reactome ID: 9607240
Reactome-version 
Reactome version: 73

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Bibliography

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  1. Klug LR, Kent JD, Heinrich MC.; ''Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases.''; PubMed Europe PMC Scholia
  2. Jayavelu AK, Müller JP, Bauer R, Böhmer SA, Lässig J, Cerny-Reiterer S, Sperr WR, Valent P, Maurer B, Moriggl R, Schröder K, Shah AM, Fischer M, Scholl S, Barth J, Oellerich T, Berg T, Serve H, Frey S, Fischer T, Heidel FH, Böhmer FD.; ''NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells.''; PubMed Europe PMC Scholia
  3. Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, Du J, Kazi JU, Luciano F, Rönnstrand L, Kung AL, Aster JC, Galinsky I, Stone RM, DeAngelo DJ, Hemann MT, Stegmaier K.; ''SYK is a critical regulator of FLT3 in acute myeloid leukemia.''; PubMed Europe PMC Scholia
  4. Richine BM, Virts EL, Bowling JD, Ramdas B, Mali R, Naoye R, Liu Z, Zhang ZY, Boswell HS, Kapur R, Chan RJ.; ''Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia.''; PubMed Europe PMC Scholia
  5. Heiss E, Masson K, Sundberg C, Pedersen M, Sun J, Bengtsson S, Rönnstrand L.; ''Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2.''; PubMed Europe PMC Scholia
  6. Daver N, Schlenk RF, Russell NH, Levis MJ.; ''Targeting FLT3 mutations in AML: review of current knowledge and evidence.''; PubMed Europe PMC Scholia
  7. Burgering BM.; ''A brief introduction to FOXOlogy.''; PubMed Europe PMC Scholia
  8. Dosil M, Wang S, Lemischka IR.; ''Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells.''; PubMed Europe PMC Scholia
  9. Kazi JU, Rönnstrand L.; ''FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia.''; PubMed Europe PMC Scholia
  10. Kazi JU, Rönnstrand L.; ''The role of SRC family kinases in FLT3 signaling.''; PubMed Europe PMC Scholia
  11. Stirewalt DL, Meshinchi S, Kussick SJ, Sheets KM, Pogosova-Agadjanyan E, Willman CL, Radich JP.; ''Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia.''; PubMed Europe PMC Scholia
  12. Grafone T, Palmisano M, Nicci C, Storti S.; ''An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment.''; PubMed Europe PMC Scholia
  13. Troadec E, Dobbelstein S, Bertrand P, Faumont N, Trimoreau F, Touati M, Chauzeix J, Petit B, Bordessoule D, Feuillard J, Bastard C, Gachard N.; ''A novel t(3;13)(q13;q12) translocation fusing FLT3 with GOLGB1: toward myeloid/lymphoid neoplasms with eosinophilia and rearrangement of FLT3?''; PubMed Europe PMC Scholia
  14. Mitina O, Warmuth M, Krause G, Hallek M, Obermeier A.; ''Src family tyrosine kinases phosphorylate Flt3 on juxtamembrane tyrosines and interfere with receptor maturation in a kinase-dependent manner.''; PubMed Europe PMC Scholia
  15. Takahashi S, Harigae H, Kaku M, Sasaki T, Licht JD.; ''Flt3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5.''; PubMed Europe PMC Scholia
  16. Loreto MP, Berry DM, McGlade CJ.; ''Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor signaling.''; PubMed Europe PMC Scholia
  17. Baldwin BR, Li L, Tse KF, Small S, Collector M, Whartenby KA, Sharkis SJ, Racke F, Huso D, Small D.; ''Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease.''; PubMed Europe PMC Scholia
  18. Lees SJ, Childs TE, Booth FW.; ''Age-dependent FOXO regulation of p27Kip1 expression via a conserved binding motif in rat muscle precursor cells.''; PubMed Europe PMC Scholia
  19. Vu HA, Xinh PT, Masuda M, Motoji T, Toyoda A, Sakaki Y, Tokunaga K, Sato Y.; ''FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation.''; PubMed Europe PMC Scholia
  20. 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
  21. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T.; ''Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product.''; PubMed Europe PMC Scholia
  22. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  23. Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, Steffen B, Matsumura I, Kanakura Y, Böhmer FD, Müller-Tidow C, Berdel WE, Serve H.; ''Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.''; PubMed Europe PMC Scholia
  24. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T.; ''Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.''; PubMed Europe PMC Scholia
  25. Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, Gilliland DG.; ''Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD.''; PubMed Europe PMC Scholia
  26. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  27. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  28. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
  29. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J.; ''Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.''; PubMed Europe PMC Scholia
  30. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  31. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; 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. Kazi JU, Kabir NN, Flores-Morales A, Rönnstrand L.; ''SOCS proteins in regulation of receptor tyrosine kinase signaling.''; PubMed Europe PMC Scholia
  34. Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM.; ''A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.''; PubMed Europe PMC Scholia
  35. Jawhar M, Naumann N, Knut M, Score J, Ghazzawi M, Schneider B, Kreuzer KA, Hallek M, Drexler HG, Chacko J, Wallis L, Fabarius A, Metzgeroth G, Hofmann WK, Chase A, Tapper W, Reiter A, Cross NCP.; ''Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia.''; PubMed Europe PMC Scholia
  36. Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ.; ''Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1).''; PubMed Europe PMC Scholia
  37. Staudt D, Murray HC, McLachlan T, Alvaro F, Enjeti AK, Verrills NM, Dun MD.; ''Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance.''; PubMed Europe PMC Scholia
  38. Peschel I, Podmirseg SR, Taschler M, Duyster J, Götze KS, Sill H, Nachbaur D, Jäkel H, Hengst L.; ''FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia.''; PubMed Europe PMC Scholia
  39. Falchi L, Mehrotra M, Newberry KJ, Lyle LM, Lu G, Patel KP, Luthra R, Popat U, Verstovsek S.; ''ETV6-FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant.''; PubMed Europe PMC Scholia
  40. Scheijen B, Ngo HT, Kang H, Griffin JD.; ''FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins.''; PubMed Europe PMC Scholia
  41. Zhang S, Broxmeyer HE.; ''p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells.''; PubMed Europe PMC Scholia
  42. Huang K, Yang M, Pan Z, Heidel FH, Scherr M, Eder M, Fischer T, Büsche G, Welte K, von Neuhoff N, Ganser A, Li Z.; ''Leukemogenic potency of the novel FLT3-N676K mutant.''; PubMed Europe PMC Scholia
  43. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  44. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  45. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  46. Quentmeier H, Reinhardt J, Zaborski M, Drexler HG.; ''FLT3 mutations in acute myeloid leukemia cell lines.''; PubMed Europe PMC Scholia
  47. Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel EM, Waddell MB, Jäkel H, Kullmann M, Kriwacki RW, Hengst L.; ''Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases.''; PubMed Europe PMC Scholia
  48. Marhäll A, Kazi JU, Rönnstrand L.; ''The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation.''; PubMed Europe PMC Scholia
  49. Okada K, Nogami A, Ishida S, Akiyama H, Chen C, Umezawa Y, Miura O.; ''FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway.''; PubMed Europe PMC Scholia
  50. Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwäble J, Buerger H, Müller-Tidow C, Choudhary C, McMahon M, Berdel WE, Serve H.; ''Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation.''; PubMed Europe PMC Scholia
  51. Lv K, Jiang J, Donaghy R, Riling CR, Cheng Y, Chandra V, Rozenova K, An W, Mohapatra BC, Goetz BT, Pillai V, Han X, Todd EA, Jeschke GR, Langdon WY, Kumar S, Hexner EO, Band H, Tong W.; ''CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies.''; PubMed Europe PMC Scholia
  52. Razumovskaya E, Masson K, Khan R, Bengtsson S, Rönnstrand L.; ''Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation.''; PubMed Europe PMC Scholia
  53. Nordigården A, Kraft M, Eliasson P, Labi V, Lam EW, Villunger A, Jönsson JI.; ''BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.''; PubMed Europe PMC Scholia
  54. Zhang H, Paliga A, Hobbs E, Moore S, Olson S, Long N, Dao KT, Tyner JW.; ''Two myeloid leukemia cases with rare FLT3 fusions.''; PubMed Europe PMC Scholia
  55. Reindl C, Bagrintseva K, Vempati S, Schnittger S, Ellwart JW, Wenig K, Hopfner KP, Hiddemann W, Spiekermann K.; ''Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.''; PubMed Europe PMC Scholia
  56. Chougule RA, Cordero E, Moharram SA, Pietras K, Rönnstrand L, Kazi JU.; ''Expression of GADS enhances FLT3-induced mitogenic signaling.''; PubMed Europe PMC Scholia
  57. Fröhling S, Scholl C, Levine RL, Loriaux M, Boggon TJ, Bernard OA, Berger R, Döhner H, Döhner K, Ebert BL, Teckie S, Golub TR, Jiang J, Schittenhelm MM, Lee BH, Griffin JD, Stone RM, Heinrich MC, Deininger MW, Druker BJ, Gilliland DG.; ''Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.''; PubMed Europe PMC Scholia
  58. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME.; ''Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.''; PubMed Europe PMC Scholia
  59. Zhang X, Song M, Kundu JK, Lee MH, Liu ZZ.; ''PIM Kinase as an Executional Target in Cancer.''; PubMed Europe PMC Scholia
  60. Chonabayashi K, Hishizawa M, Kawamata S, Nagai Y, Ohno T, Ishikawa T, Uchiyama T, Takaori-Kondo A.; ''Direct binding of Grb2 has an important role in the development of myeloproliferative disease induced by ETV6/FLT3.''; PubMed Europe PMC Scholia
  61. Grand FH, Iqbal S, Zhang L, Russell NH, Chase A, Cross NC.; ''A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy.''; PubMed Europe PMC Scholia
  62. Schittenhelm MM, Yee KW, Tyner JW, McGreevey L, Haley AD, Town A, Griffith DJ, Bainbridge T, Braziel RM, O'Farrell AM, Cherrington JM, Heinrich MC.; ''FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248).''; PubMed Europe PMC Scholia
  63. Sargin B, Choudhary C, Crosetto N, Schmidt MHH, Grundler R, Rensinghoff M, Thiessen C, Tickenbrock L, Schwäble J, Brandts C, August B, Koschmieder S, Bandi SR, Duyster J, Berdel WE, Müller-Tidow C, Dikic I, Serve H.; ''Flt3-dependent transformation by inactivating c-Cbl mutations in AML.''; PubMed Europe PMC Scholia
  64. Lim SH, Dubielecka PM, Raghunathan VM.; ''Molecular targeting in acute myeloid leukemia.''; PubMed Europe PMC Scholia
  65. Spiekermann K, Bagrintseva K, Schwab R, Schmieja K, Hiddemann W.; ''Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells.''; PubMed Europe PMC Scholia
  66. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG.; ''FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model.''; PubMed Europe PMC Scholia
  67. Chung A, Hou Y, Ohgami RS, Von Gehr A, Fisk DG, Roskin KM, Li X, Gojenola L, Bangs CD, Arber DA, Fire AZ, Cherry AM, Zehnder JL, Gotlib J, Merker JD.; ''A novel TRIP11-FLT3 fusion in a patient with a myeloid/lymphoid neoplasm with eosinophilia.''; PubMed Europe PMC Scholia
  68. Medema RH, Kops GJ, Bos JL, Burgering BM.; ''AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.''; PubMed Europe PMC Scholia
  69. Kazi JU, Vaapil M, Agarwal S, Bracco E, Påhlman S, Rönnstrand L.; ''The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling.''; PubMed Europe PMC Scholia
  70. Breitenbuecher F, Schnittger S, Grundler R, Markova B, Carius B, Brecht A, Duyster J, Haferlach T, Huber C, Fischer T.; ''Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor.''; PubMed Europe PMC Scholia
  71. Choudhary C, Brandts C, Schwable J, Tickenbrock L, Sargin B, Ueker A, Böhmer FD, Berdel WE, Müller-Tidow C, Serve H.; ''Activation mechanisms of STAT5 by oncogenic Flt3-ITD.''; PubMed Europe PMC Scholia
  72. Williams AB, Nguyen B, Li L, Brown P, Levis M, Leahy D, Small D.; ''Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors.''; PubMed Europe PMC Scholia
  73. Burke JE, Vadas O, Berndt A, Finegan T, Perisic O, Williams RL.; ''Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α.''; PubMed Europe PMC Scholia
  74. Dragone LL, Myers MD, White C, Gadwal S, Sosinowski T, Gu H, Weiss A.; ''Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner.''; PubMed Europe PMC Scholia
  75. Yadav RK, Chauhan AS, Zhuang L, Gan B.; ''FoxO transcription factors in cancer metabolism.''; PubMed Europe PMC Scholia
  76. Arnaud M, Crouin C, Deon C, Loyaux D, Bertoglio J.; ''Phosphorylation of Grb2-associated binder 2 on serine 623 by ERK MAPK regulates its association with the phosphatase SHP-2 and decreases STAT5 activation.''; PubMed Europe PMC Scholia
  77. Reddy MM, Fernandes MS, Salgia R, Levine RL, Griffin JD, Sattler M.; ''NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases.''; PubMed Europe PMC Scholia
  78. Voisset E, Lopez S, Chaix A, Georges C, Hanssens K, Prébet T, Dubreuil P, De Sepulveda P.; ''FES kinases are required for oncogenic FLT3 signaling.''; PubMed Europe PMC Scholia
  79. Kresinsky A, Bauer R, Schnöder TM, Berg T, Meyer D, Ast V, König R, Serve H, Heidel FH, Böhmer FD, Müller JP.; ''Loss of DEP-1 (Ptprj) promotes myeloproliferative disease in FLT3-ITD acute myeloid leukemia.''; PubMed Europe PMC Scholia
  80. Vu HA, Xinh PT, Kano Y, Tokunaga K, Sato Y.; ''The juxtamembrane domain in ETV6/FLT3 is critical for PIM-1 up-regulation and cell proliferation.''; PubMed Europe PMC Scholia
  81. Clark JJ, Cools J, Curley DP, Yu JC, Lokker NA, Giese NA, Gilliland DG.; ''Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518.''; PubMed Europe PMC Scholia
  82. Zhang S, Broxmeyer HE.; ''Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase.''; PubMed Europe PMC Scholia
  83. Mathias TJ, Natarajan K, Shukla S, Doshi KA, Singh ZN, Ambudkar SV, Baer MR.; ''The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations.''; PubMed Europe PMC Scholia
  84. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M.; ''Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.''; PubMed Europe PMC Scholia
  85. Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M, Small D.; ''Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival.''; PubMed Europe PMC Scholia
  86. Kazi JU, Rupar K, Marhäll A, Moharram SA, Khanum F, Shah K, Gazi M, Nagaraj SR, Sun J, Chougule RA, Rönnstrand L.; ''ABL2 suppresses FLT3-ITD-induced cell proliferation through negative regulation of AKT signaling.''; PubMed Europe PMC Scholia
  87. Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J.; ''Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.''; PubMed Europe PMC Scholia
  88. Kazi JU, Sun J, Phung B, Zadjali F, Flores-Morales A, Rönnstrand L.; ''Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3.''; PubMed Europe PMC Scholia
  89. Jayavelu AK, Moloney JN, Böhmer FD, Cotter TG.; ''NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML.''; PubMed Europe PMC Scholia
  90. Kazi JU, Rönnstrand L.; ''FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications.''; PubMed Europe PMC Scholia
  91. Masson K, Liu T, Khan R, Sun J, Rönnstrand L.; ''A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival.''; PubMed Europe PMC Scholia
  92. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  93. Rani A, Murphy JJ.; ''STAT5 in Cancer and Immunity.''; PubMed Europe PMC Scholia
  94. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  95. Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Müller C, Grüning W, Kratz-Albers K, Serve S, Steur C, Büchner T, Kienast J, Kanakura Y, Berdel WE, Serve H.; ''Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways.''; PubMed Europe PMC Scholia
  96. Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T.; ''STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells.''; PubMed Europe PMC Scholia
  97. Moharram SA, Chougule RA, Su X, Li T, Sun J, Zhao H, Rönnstrand L, Kazi JU.; ''Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling.''; PubMed Europe PMC Scholia
  98. Jiang J, Paez JG, Lee JC, Bo R, Stone RM, DeAngelo DJ, Galinsky I, Wolpin BM, Jonasova A, Herman P, Fox EA, Boggon TJ, Eck MJ, Weisberg E, Griffin JD, Gilliland DG, Meyerson M, Sellers WR.; ''Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML.''; PubMed Europe PMC Scholia
  99. Reindl C, Quentmeier H, Petropoulos K, Greif PA, Benthaus T, Argiropoulos B, Mellert G, Vempati S, Duyster J, Buske C, Bohlander SK, Humphries KR, Hiddemann W, Spiekermann K.; ''CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes.''; PubMed Europe PMC Scholia
  100. Lin DC, Yin T, Koren-Michowitz M, Ding LW, Gueller S, Gery S, Tabayashi T, Bergholz U, Kazi JU, Rönnstrand L, Stocking C, Koeffler HP.; ''Adaptor protein Lnk binds to and inhibits normal and leukemic FLT3.''; PubMed Europe PMC Scholia
  101. Sallmyr A, Fan J, Datta K, Kim KT, Grosu D, Shapiro P, Small D, Rassool F.; ''Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML.''; PubMed Europe PMC Scholia
  102. Arora D, Stopp S, Böhmer SA, Schons J, Godfrey R, Masson K, Razumovskaya E, Rönnstrand L, Tänzer S, Bauer R, Böhmer FD, Müller JP.; ''Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling.''; PubMed Europe PMC Scholia
  103. Kazi JU, Rönnstrand L.; ''Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling.''; PubMed Europe PMC Scholia
  104. Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M.; ''Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.''; PubMed Europe PMC Scholia
  105. Kazi JU, Rönnstrand L.; ''Src-Like adaptor protein (SLAP) binds to the receptor tyrosine kinase Flt3 and modulates receptor stability and downstream signaling.''; PubMed Europe PMC Scholia
  106. Nabinger SC, Li XJ, Ramdas B, He Y, Zhang X, Zeng L, Richine B, Bowling JD, Fukuda S, Goenka S, Liu Z, Feng GS, Yu M, Sandusky GE, Boswell HS, Zhang ZY, Kapur R, Chan RJ.; ''The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo.''; PubMed Europe PMC Scholia
  107. Ray A, James MK, Larochelle S, Fisher RP, Blain SW.; ''p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes.''; PubMed Europe PMC Scholia
  108. Reiter A, Gotlib J.; ''Myeloid neoplasms with eosinophilia.''; PubMed Europe PMC Scholia
  109. Leischner H, Albers C, Grundler R, Razumovskaya E, Spiekermann K, Bohlander S, Rönnstrand L, Götze K, Peschel C, Duyster J.; ''SRC is a signaling mediator in FLT3-ITD- but not in FLT3-TKD-positive AML.''; PubMed Europe PMC Scholia
  110. Arrouchi H, Lakhlili W, Ibrahimi A.; ''A review on PIM kinases in tumors.''; PubMed Europe PMC Scholia
  111. Walz C, Erben P, Ritter M, Bloor A, Metzgeroth G, Telford N, Haferlach C, Haferlach T, Gesk S, Score J, Hofmann WK, Hochhaus A, Cross NC, Reiter A.; ''Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3.''; PubMed Europe PMC Scholia
  112. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  113. Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN.; ''Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.''; PubMed Europe PMC Scholia
  114. Yee KW, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL, McGreevey LS, Griffith DJ, Heinrich MC.; ''SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  115. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, Naoe T.; ''Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines.''; PubMed Europe PMC Scholia
  116. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  117. Chougule RA, Kazi JU, Rönnstrand L.; ''FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia.''; PubMed Europe PMC Scholia
  118. Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC, Beran M, Zhu Z, Ludwig D, Hicklin D, Witte L, Li Y, Small D.; ''FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells.''; PubMed Europe PMC Scholia
  119. Larrosa-Garcia M, Baer MR.; ''FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions.''; PubMed Europe PMC Scholia
  120. Bertoli S, Boutzen H, David L, Larrue C, Vergez F, Fernandez-Vidal A, Yuan L, Hospital MA, Tamburini J, Demur C, Delabesse E, Saland E, Sarry JE, Galcera MO, Mansat-De Mas V, Didier C, Dozier C, Récher C, Manenti S.; ''CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia.''; PubMed Europe PMC Scholia
  121. Godfrey R, Arora D, Bauer R, Stopp S, Müller JP, Heinrich T, Böhmer SA, Dagnell M, Schnetzke U, Scholl S, Östman A, Böhmer FD.; ''Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ.''; PubMed Europe PMC Scholia

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

View all...
NameTypeDatabase referenceComment
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:HCKComplexR-HSA-9609280 (Reactome)
Active FLT3:PTPN11ComplexR-HSA-9604972 (Reactome)
Active FLT3ComplexR-HSA-9604751 (Reactome)
Autophosphorylated FLT3 ProteinP36888 (Uniprot-TrEMBL)
FLT3 ProteinP36888 (Uniprot-TrEMBL)
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)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GAB2ProteinQ9UQC2 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HCK ProteinP08631 (Uniprot-TrEMBL)
HCKProteinP08631 (Uniprot-TrEMBL)
PI3K CascadePathwayR-HSA-109704 (Reactome) The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival.
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
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).
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)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (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.
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9604767 (Reactome)
ADPArrowR-HSA-9606622 (Reactome)
ATPR-HSA-9604767 (Reactome)
ATPR-HSA-9606622 (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: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: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)
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 dimerR-HSA-6786789 (Reactome)
FLT3R-HSA-6786789 (Reactome)
FLT3R-HSA-8854736 (Reactome)
FYNR-HSA-9605259 (Reactome)
GAB2R-HSA-9606624 (Reactome)
GDPArrowR-HSA-9607304 (Reactome)
GRB2-1R-HSA-9604738 (Reactome)
GTPR-HSA-9607304 (Reactome)
HCKR-HSA-9609274 (Reactome)
PIK3R1R-HSA-9607224 (Reactome)
PTPN11R-HSA-9604969 (Reactome)
PTPN11R-HSA-9606784 (Reactome)
R-HSA-6786789 (Reactome) FLT3 is a member of the Class III Receptor Tyrosine Kinase Family, which also includes FMS, 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. 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.
SOS1R-HSA-9607301 (Reactome)
p21 RAS:GDPR-HSA-9607304 (Reactome)
p21 RAS:GTPArrowR-HSA-9607304 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5016"
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