Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells.

Abstract

Interleukin 4 (IL-4), insulin, and insulin-like growth factor I (IGF-I) efficiently induced DNA synthesis in the IL-3-dependent murine myeloid cell lines FDC-P1 and FDC-P2. Although these factors could not individually sustain long-term growth of these lines, a combination of IL-4 with either insulin or IGF-I did support continuous growth. The principal tyrosine-phosphorylated substrate observed in FDC cells stimulated with IL-4, previously designated 4PS, was of the same size (170 kDa) as the major substrate phosphorylated in response to insulin or IGF-I. These substrates had phosphopeptides of the same size when analyzed by digestion with Staphylococcus aureus V8 protease, and each tightly associated with the 85-kDa component of phosphatidylinositol 3-kinase after factor stimulation. IRS-1, the principal substrate phosphorylated in response to insulin or IGF-I stimulation in nonhematopoietic cells, is similar in size to 4PS. However, anti-IRS-1 antibodies failed to efficiently precipitate 4PS, and some phosphopeptides generated by V8 protease digestion of IRS-1 were distinct in size from the phosphopeptides of 4PS. Nevertheless, IL-4, insulin, and IGF-I were capable of stimulating tyrosine phosphorylation of IRS-1 in FDC cells that expressed this substrate as a result of transfection. These rmdings indicate that (i) IL-4, insulin, and IGF-I use signal transduction pathways in FDC lines that have at least one major feature in common, the rapid tyrosine phosphorylation of 4PS, and (it) insulin and IGF

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

“…The MyD88-independent signaling pathways preferentially eliciting development of Th2-biased responses are not well characterized. Our results clearly implicate p110d as a major signaling axis in Th2 induction.Signaling through the IL-4 receptor is known to activate PI3K signaling [30,31], and we have recently shown a requirement for p110d in IL-4 signaling in B cells [18]. The phenotype we describe here is similar to that seen in STAT6-deficient mice, which are defective in IL-4 signaling [32,33].…”

The phosphatidylinositol 3′ kinase pathway is required for the survival signal of leukocyte tyrosine kinase

“…We ®rst intended to characterize the survival signal transmitted via IRS-1. Because insulin or IL-4 induces tyrosine phosphorylation of IRS-1 and its association with the p85 subunit of PI3 kinase Myers et al, 1993Myers et al, , 1994Wang et al, 1993), we tested if wortmannin, a speci®c inhibitor for PI3 kinase, a ects the survival signal of LTK. We have established EL, which is a stable line of Ba/F3 cells expressing the EGF receptor-LTK chimeric receptor and EL-Y862F, which expresses the mutant chimeric receptors in which the indicated tyrosine is mutated to phenylalanine.…”

“…Recently it was reported that the phosphatidylinositol 3' (PI3)-kinase pathway is required for survival signals of trk and PDGF receptor (Yao and Cooper, 1995;. Because IRS-1 is known to associate with the p85 subunit of PI3 kinase when phosphorylated by insulin or interleukin 4 Myers et al, 1993Myers et al, , 1994Wang et al, 1993), we hypothesized that the PI3 kinase pathway plays an important role in anti-apoptotic e ects of LTK. Moreover, we found that c-Cbl proto-oncogene product is phosphorylated on tyrosine residues by LTK.…”

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

“…In ®broblasts, IL-4 modulates functional responses such as extracellular matrix production (Postlethwaite et al, 1992) and chemotaxis (Postlethwaite and Seyer, 1991), rather than inducing pronounced proliferative e ects (Postlethwaite et al, 1992). IL-4R activation (Wang et al, 1992) results in tyrosine phosphorylation of many signaling molecules including Jak1, Jak3 (Johnston et al, 1994;Witthuhn et al, 1994), IRS-1 (Wang et al, 1993b), IRS-2/4PS (Wang et al, 1993a), and Stat6 (Hou et al, 1994;Kotanides and Reich, 1993;Quelle et al, 1995;Schindler and Darnell, 1995). In Stat6 de®cient mice, IL-4-induced proliferation of T cells as well as B cells after IgM stimulation was dramatically reduced (Kaplan et al, 1996;Shimoda et al, 1996;Takeda et al 1996).…”