SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor

Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain

“…However, when the length of the JM In all transformed 32D cells analysed here, mutant-FLT3 was dimerized, and MAP kinase and STAT5a were constitutively activated in accordance with our previous study in FLT3/ITD-expressing 32D cells (Hayakawa et al, 2000). In addition, we demonstrated the constitutive activation of SHC, which has been reportedly activated by Wt-FLT3 in a FL-dependent manner (Marchetto et al, 1999). These results indicated that signal-transduction cascades following the activation of mutant FLT3 might be the same, and that no positively regulating molecules seemed to be recruited to the tyrosine residues within the JM domain.…”

“…In all transformed 32D cells, MAP kinase and STAT5a were constitutively activated consistent with our previous study in FLT3/ITDexpressing 32D cells (Figure 4). In addition, we demonstrated the constitutive activation of SHC, which has been reported to be activated in an FL-dependent manner (Marchetto et al, 1999) (Figure 4). It should be noted that in the Wt-FLT3-expressing 32D cells, the phosphorylation of STAT5a was not detected even after FL-stimulation in contrast to the FL-dependent phosphorylation of MAPK and SHC.…”

“…Previous work demonstrated that SHP1 was neither activated nor recruited by the activated FLT3 (Zhang et al, 1999). Recently, it was demonstrated that overexpressed SHC negatively regulated cell growth induced by FLT3 activation (Marchetto et al, 1999). However, expressing and phosphorylation status were the same among Wt-and mutant-FLT3-transfected 32D cells.…”

FLT3: ITDoes matter in leukemia

“…For example, wild-type FLT3 has been shown to signal through Ras-GAP, PI3-kinase, Grb2, SHP-2, Shc, and Vav. [32][33][34][35][36][37] Constitutively activated FLT3, expressed in murine cell lines, has likewise been demonstrated to activate MAP kinase (presumably via Ras activation) and AKT (downstream of PI3-kinase). 88,89 However, in these experimental systems, Jak2, STAT3, and CBL were also identified as activated by constitutively activated FLT3, but not by wild-type FLT3.…”

A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy

“…10 Both types of mutation cause autophosphorylation of the receptor, leading to activation of downstream signaling pathways involved in regulation of transcription, proliferation, and apoptosis. [11][12][13] The overexpressed wild-type (WT) FLT3 receptor may also be activated in AML cells by endogenous coexpression of the FLT3 ligand. 14,15 FLT3 in both its mutated and WT configurations may thus contribute significantly to leukemogenesis, although for AML to occur, at least 1 further molecular event that is inhibitory to cell differentiation is likely to be required.…”