Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs

Abstract

The FLT3/FLK2 receptor tyrosine kinase is closely related to two receptors, c-Kit and c-Fms, which function with their respective ligands, Kit ligand and macrophage colony-stimulating factor to control differentiation of haematopoietic and non-haematopoietic cells. FLT3/FLK2 is thought to be present on haematopoietic stem cells and found in brain, placenta and testis. We have purified to homogeneity and partially sequenced a soluble form of the FLT3/FLK2 ligand produced by mouse thymic stromal cells. We isolated several mouse and human complementary DNAs that encode polypeptides with identical N termini and different C termini. Some variants contain hydrophobic transmembrane segments, suggesting that processing may be required to release soluble ligand. The purified ligand enhances the response of mouse stem cells and a primitive human progenitor cell population to other growth factors such as interleukins IL-3 and IL-6 and to granulocyte-macrophage colony-stimulating factor, and also stimulates fetal thymocytes.

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…The receptor becomes autophosphorylated, inducing cell growth and inhibiting apoptosis through the activation of a signaling cascade involving proteins such as the Ras-GTPase-activating protein, phospholipase C, signal transducer and activator of transcription 5 and ERK1/2 ( Figure 1). 18 Whereas, FLT3 ligand is ubiquitously expressed, 19,20 the FLT3 receptor is localized primarily in hematopoietic and neural tissues. 21 FLT3 is integral to hematopoiesis through its regulation of proliferation, differentiation and apoptosis of hematopoietic progenitor cells.…”

Specific and common activities of the FLT3 and KIT tyrosine kinase receptors revealed by the use of cultured mast cells

“…10,11,[57][58][59] The costimulation of cultured mast cells with KL and IL3 led to a In vitro maturation of mast cells monitored by expression of mast cell proteases. Samples of total RNA extracted from vectorinfected or FF3-infected FLM cells cultured in the presence of IL3 (1% of X63-CM), KL (250 ng/ml) and CSF1 (200 ng/ml) were subjected to RT-PCR (35 cycles) with primer sets specific for the different mast cell proteases.…”

“…FLT3 and KIT are expressed on highly enriched hematopoietic stem cell populations (HSC) [7][8][9][10][11] and each of them may participate in the activation of lineage-specific developmental programs. FL, in combination with other cytokines such as IL7, IL11 and KL, allows the proliferation and differentiation of early B cell progenitors.…”

Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells

“…Soluble forms activate the corresponding FLT3 receptor [3] Although its messenger RNA is detected in most hematopoietic and nonhematopoietic tissues, protein expression is restricted to T lymphocytes and BM stromal cells composing the hematopoietic microenvironment [15][16][17]. Generally, FL acts in combination with other cytokines, resulting in strongly synergistic effects; isolated addition of FL to stem/progenitor cell cultures has no significant effect on proliferation of myeloid and lymphoid progenitors [18][19][20][21].…”