in 1991 and is located on chromosome 13q12 in humans. The protein contains 993 amino acids and lt is visualized as a doublet consisting of a mature Address correspondence to this author at the Kimmel Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 243, Baltimore, MD 21231, USA, Tel: PCI-34051 410 502 3629, Fax: 410 614 7279, @ levisma jhmi. NIH Public Access Author Manuscript Curr Drug Targets. Author manuscript, increases available in PMC 20th January 2011. Ver published in its final form: Curr Drug Targets. July 2010, 11: 781,789th and form an immature form, on electrophoresis gels. Lt contains An extracellular Re cathedral Ne FLT3-ligand binding, a transmembrane Ne and intracellular R, a juxtamembrane Dom Cathedral ne and the tyrosine kinase sharing plans.
The kinase-ne Cathedral is interrupted by a short hydrophilic sequence of the insert, so that FLT3 be classified with a group of RTK that share this structural feature: KIT, FMS, PDGF-R and VEGF-receptors. The homology within the family of split-kinase-Dom Ne RTK divided explained Rt why small-molecule inhibitors of FLT3 activity have often GDC-0449 strong t against these other receptors. The juxtamembrane Cathedral Ne of FLT3, as in many other receptors, exerts a negative influence on the regulation of tyrosine kinase activity of t. Ren can juxtamembrane region mutations in the st Its negative regulatory functions, and this area is the location of the h Most common and most important FLT3-activating mutations, internal tandem duplication mutations which, discovered in 1996.
Activating point mutations in the kinase-Dom Ne were discovered in 2001. After binding of the ligand to FLT3, FLT3 dimerizes, which in turn causes a conformational then Change only in the activation loop, access to the ATP binding site FLT3 connection. The receptor dimerizes erf Leads autophosphorylation and subsequently End converts signals via its kinase activity T, in a manner to inhibit apoptosis and differentiation and f Rdern proliferation. Proteins Z in these ways Select Ras GAP, PLC, ERK1 / 2, PI3K/AKT, FOXO proteins PIM1 and PIM2 and. FLT3 has a relatively narrow range of cellular Ren expression and Haupt you Chlich in h Localized hematopoietic tissues Ethical and nerves, which probably limits their capabilities in these cell types.
In the bone marrow in FLT3 h Expressed hematopoietic cell fraction Ethical CD34, CD34, and a smaller proportion of � Cells destined to become dendritic cells. However, its ligands in nearly all cell types studied so far expressed. FL acts synergistically with other cytokines, the expansion of h rdern Hematopoietic precursor Shore f Ethical, and targeted destruction Tion either FLT3 or FL in M Mice leads to a reduction in hours Hematopoietic precursor Shore Ethical. FLT3 � � Develop M Mice are normal with only slight h Dermatological dyscrasias mainly do the B-cell-line pharmacological suggesting specific targeting FLT3 have limited toxicity t k can. FLT3 ITD signaling aberrations are associated with have been described and are somewhat different than in the FLT3 tyrosine kinase Dom Found A mutants.
FLT3 ITD with activation of STAT5 activation and repression of transcription downstream Rts PU.1 All WT and FLT3 or FLT3 TKD CEBP is associated not activated STAT5. There are no significant differences in the FLT3-ITD signaling through ERK1 / 2, AKT, or Shc. Deviation are signaling not only from the type of mutation associated, but also seems related to FLT3 ITD intracellular position Re. FLT3 in leukemia Chemistry FLT3, the receptor is on blasts in most cases expressed Of AML, but not