Stem Cell Factor Synergistically Enhances Thrombopoietin‐Induced STAT5 Signaling in Megakaryocyte Progenitors through JAK2 and Src Kinase

Abstract

Stem cell factor (SCF) has a potent synergistic effect during megakaryopoiesis when administered in combination with the major megakaryocytic cytokine, thrombopoietin (TPO). In this study we analyzed the underlying mechanisms with regard to STAT5 activity. TPO stimulation of MO7e cells resulted in STAT5 transactivation, which could be enhanced 1.6-fold by costimulation with SCF, whereas SCF alone did not induce STAT5 transcriptional activity. This costimulatory effect of SCF was reflected in an increase in TPO-induced STAT5 DNA binding and increased and prolonged STAT5 tyrosine phosphorylation in both MO7e cells and primary human megakaryocyte progenitors. In contrast, serine phosphorylation of STAT5 was constitutive and associated with an inhibitory effect on STAT5 transactivation. Signal transduction pathways that might synergize in TPO-mediated STAT5 transactivation were analyzed using specific pharmacological inhibitors and indicated an essential role for Janus-activated kinase 2 (JAK2) and a partial role for Src-family kinases. Costimulation with SCF was found to increase and prolong tyrosine phosphorylation of JAK2 and the TPO receptor c-mpl. In addition, the Src kinase inhibitor SU6656 partially downregulated the additional effect of SCF costimulation on STAT5 tyrosine phosphorylation. SCF-induced enhancement of JAK2 phosphorylation was not affected by inhibition of Src kinase, suggesting that both JAK2 and Src kinase mediate STAT5 tyrosine phosphorylation. Synergistic activation of JAK2 and Src kinase may thus contribute to the enhanced STAT5 signaling in the presence of TPO and SCF. Stem Cells 2005;23:240-251

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…The analysis of downstream pathways commonly activated upon PDGFR activation showed that activation of the SRC family of kinases and the JAK2/STAT5 signaling pathways were both involved in RA-induced gonocyte differentiation (Manku et al 2014). Considering that STAT5 is a possible downstream target of SRC (Drayer et al 2005), it will be important to determine whether it is activated via JAK2, SRC, or another pathway in gonocytes. The presence of a variant PDGFRA form in gonocytes is interesting in view of the existence of a similar variant transcript identified in seminomas, the most common type of TGCTs (Palumbo et al 2002), and because of the possible relationship between improper gonocyte development and TGCT formation (Rajpert-De Meyts & Hoei-Hansen 2007).…”

Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

“…The ligand for KIT receptor is the stem cell factor (SCF) also known as KIT ligand, steel factor and mast cell growth factor. SCF is implicated in cell proliferation (Williams and Allan, 1996;Drayer et al, 2005), migration and survival (Bredin et al, 2003;Erlandsson et al, 2004). Recently, SCF has also been shown to be implicated in a resistance mechanism of malignant mesothelioma cells to drug treatment (Catalano et al, 2004).…”

Psidium Guajava L. Extract Increases Platelet Count Through Enhancement of Stem Cell Factor Expression in Thrombocytopenic Mice Model

“…The increase in a number of platelets increased count may be due to the rise of several molecules such as SCF [4]. To determine the molecular mechanism of platelet production in mice model after treatment with guava extract, we evaluated the expression of SCF mRNA using qRT-PCR.…”

“…Platelet generation is a two-stage process consisting of megakaryopoiesis and thrombopoiesis [4]. Megakaryopoiesis is a complex process that involves differentiation of hematopoietic stem cells (HSCs) to the megakaryocyte (MK), the proliferation of the progenitors, and MK maturation [18].…”

“…Stem cell factor (SCF) and thrombopoietin (TPO) are critical cytokines in regulating stem cell proliferation and survival of progenitor cell during hematopoiesis. In addition, TPO is an important megakaryocytic cytokine affecting the megakaryocytic differentiation [4]. per liter [2].…”