FLT3 Signaling in Hematopoietic Progenitor Cells

Fms-like tyrosine kinase-3 (FLT3), also known as fetal liver kinase-2 (FLK2) and STK1 was originally isolated as a hematopoietic progenitor cell-specific kinase and belongs to the Class-III RTK family (c-Fms, c-Kit, PDGFR). FLT3 is normally expressed in hemopoietic progenitor cells in the bone marrow, thymus and lymph nodes, though it is also found in other tissues such as placenta, brain, cerebellum and gonads. Aberrantly expressed FLT3 is observed at high levels in a spectrum of hematologic malignancies like Acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemia (ALL), a fraction of T-Cell ALL, and Chronic myelogenous leukemia (CML) in lymphoid blast crisis. Human FLT3 is a 160 kDa, type I transmembrane glycoprotein whose ligand (FLT3L) is expressed by marrow stromal cells and other cells. In synergy with other growth factors, FLT3L/FLT3 stimulate the proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells. Interaction of FLT3 with its ligand results in receptor dimerization, autophosphorylation and the subsequent phosphorylation of cytoplasmic substrates that are involved in signaling pathways regulating the proliferation of pluripotent stem cells, early progenitor cells and immature lymphocytes. This interaction is influenced by other cytokines such as Kit ligand.FLT3 contains five extracellular immunoglobulin-like domains, a transmembrane (TM) domain, a juxtamembrane (JM) domain and two tyrosine-kinase domains (K) that are linked by the KI domain. Cytoplasmic FLT3 undergoes glycosylation, which promotes localization of the receptor to the membrane. Wild-type FLT3 remains as a monomeric, inactivated protein on the cell surface until FLT3L in a dimeric form, binds the receptor and induces receptor dimerization. FLT3 dimerization promotes phosphorylation of K, thereby activating the receptor and downstream effectors. The dimerized receptors are quickly internalized and degraded. Although the FLT3 signaling cascade has not been definitively characterized, the binding of FLT3L to FLT3 triggers the PI3K and Ras pathways, leading to increased cell proliferation and the inhibition of apoptosis.PI3K activity is regulated through various interactions between FLT3, SHCs and other proteins, such as SHIP, SHP2, Cbl and GAB2. Activated PI3K stimulates downstream proteins such as PDK1, Akt1/ PKB and mTOR, which initiate the transcription and translation of crucial regulatory genes through the activation of S6K and the inhibition of 4E-Binding Protein (4E-BP1). In addition, PI3K activation blocks apoptosis through phosphorylation of the pro-apoptotic protein BAD. Activated FLT3 also associates with GRB2 and activates Ras stimulating downstream effectors such as Raf, MEK, p38, ERK1/2 and the 90-kDa Ribosomal protein S6 Kinase (RSK). These downstream effectors activate CREB, Elk and STAT, which lead to the expression of FLT3.Functionally, FLT3L shows marked activity on hematopoietic stem cells and thus maybe considered as a stem cell growth factor. In particular,FLT3L plays an important role in inducing the proliferation of both B-cell progenitors and later stage pro-B-cells.