Kit activates interleukin‐4 receptor and effector signal transducer and activator of transcription 6 independent of its cognate ligand in mouse mast cells

Abstract

Summary Signaling by Kit has been extensively studied in hematopoietic cells and is essential for the survival, proliferation and maintenance of hematopoietic stem and progenitor cells. In addition to the activation of intrinsic signaling pathways, Kit has been shown to interact with lineage‐restricted type I cytokine receptors and produce cross signals, e.g. erythropoietin receptor, interleukin‐7 receptor (IL‐7R), IL‐3R. Based on the earlier studies, we hypothesize that Kit activate other type I cytokine receptors in a cell‐specific manner and execute cell‐specific function. To investigate other Kit‐activated receptors, we tested Kit and IL‐4R cross‐receptor activation in murine bone‐marrow‐derived mast cells, which express both Kit and IL‐4R at the surface level. Kit upon activation by Kit ligand (KL), activated IL‐4Rα, γC, and signal transducer and activator of transcription 6 independent of its cognate ligand IL‐4. Though KL and IL‐4 are individually mitogenic, combinations of KL and IL‐4 synergistically promoted mast cell proliferation. Furthermore, inhibition of lipid raft formation by methyl‐β‐cyclodextrin resulted in loss of synergistic proliferation. Together the data suggest IL‐4R as a novel Kit‐activated receptor. Such cross‐receptor activations are likely to be a universal mechanism of Kit signaling in hematopoiesis.

Interleukin‐3 stabilizes CD124/IL‐4α surface expression in mast cells via Tyk2 and STAT6

“…Both, SCF and IL‐3 activate JAK2, a member of the JAK family, which consists of JAK1‐3 and Tyk2 [6,7]. While SCF stimulation results in downstream activation of STAT5 and STAT6 [7,8], IL‐3 preferentially activates STAT3 and STAT5 [2]. Interestingly, experiments with the IL‐3‐dependent mouse lymphoma cell line DA‐3 demonstrated that also STAT6 can be activated by IL‐3 stimulation [9], but no such data have been shown in primary cells, yet.…”

“…STAT6 has mainly been characterized as a shared downstream target of IL-4 and IL-13 [12,18]. Surprisingly, the Kit (CD117) ligand stem cell factor (SCF) can induce STAT6 activation by utilizing the IL-4R in absence of IL-4 [8]. Downstream the IL-4 receptor, several JAK kinases mediate the signal via chain-specific interactions.…”