Biological Consequences Of Flt3 Signaling

Initial studies on FLT3 signaling have been performed using chimeric receptors containing the extracellular part of human c-FMS. These activated mouse FLT3 receptors induce direct interactions with adaptor protein GRB2 and the p85 subunit of PI3K (121,122), and concomitant phosphorylation of SHIP,

SHC, Vav, RasGAP, and PLCy (121,123). FL-mediated triggering of human FLT3 receptor results in direct association with GRB2 and SOCS1, and promotes phosphorylation and complex formation of CBL, CBLB, SHC, SHIP, SHP2, GAB1, GAB2, and activation of mitogen-activated protein kinase (MAPK) pathway (124-126). In contrast to murine FLT3, human FLT3 has no consensus SH2-domain binding site for p85-PI3K in the carboxyl terminus, nor does p85 seem to be tyrosine phosphorylated on FL binding (127). Instead, p85-PI3K has been found to be associated with complexes containing tyrosine phosphorylated SHP2, SHIP, GAB1, GAB2, CBL, and CBLB (126-128).

As expected, signal transduction downstream of FLT3-ITD receptors mimics to a large extent FL-induced activation of wild-type FLT3 receptors. FLT3-ITD signaling results in complex formation with SHC, CBL, Vav, and SHP2, and constitutive activation of signaling pathways such as RAS, MAPK, signal tran-ducers and activators of transcription (STAT)3, STAT5, and AKT/PKB (82,109,110). However, there are accumulating data suggesting also differences between wild-type and mutant FLT3 signaling. For instance, FLT3-ITD mutants strongly induce STAT5 activation, which is hardly observed with FL stimulation of wild-type FLT3 receptors (109,110,129). Anti-apoptotic and pro-liferative signaling of FLT3-ITD receptors specifically correlates with induction of STAT target genes, such as Pim2, SOCS2/3, and Bcl-XL (130,131).

One characteristic feature of AML is a block in one of the different stages of myeloid differentiation, and several reports have shown that activated FLT3 signaling can directly contribute to inhibition of myeloid differentiation. Expression of FLT3-ITD prohibits G-CSF-induced differentiation of 32D cells (132), and microarray analysis has demonstrated that FLT3-ITD receptor signaling represses expression of transcription factors PU.1 and C/EBPa, which are normally required to induce myeloid differentiation (130,133).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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