Requirement of Tyrosine Phosphorylation for Rapid Activation of a DNA Binding Factor by IL-4

Abstract

Interleukin-4 (IL-4) is an immunoregulatory cytokine produced by activated T lymphocytes to promote the growth and differentiation of cells that participate in immune defense. This study demonstrates the rapid activation of a specific DNA binding factor by IL-4. The IL-4 nuclear-activated factor (IL-4 NAF) appeared within minutes of IL-4 stimulation and recognized a specific DNA sequence found in the promoters of IL-4-responsive genes. Activation of this putative transcription factor required tyrosine phosphorylation, and antibodies specific for phosphotyrosine recognize the IL-4 NAF-DNA complex. Thus, IL-4 appears to transduce a signal to the nucleus through tyrosine phosphorylation of a latent DNA binding factor.

The biology of Stat4 and Stat6

“…Early work on IL-4 signal transduction suggested that IL-4 signaling would parallel the general STAT pathway described above (Kohler and Rieber, 1993;Kotanides and Reich, 1993;Schindler et al, 1994). For example, IL-4, like other cytokines, had been found to induce rapid and speci®c gene activation events within hours of cytokine stimulation.…”

“…The protein that bound to the site was tyrosine phosphorylated in response to IL-4 and shared homology with other known STAT proteins in its proposed DNA binding, SH3 and SH2 domains. The protein was termed by several groups STF-IL-4, IL-4 STAT, IL-4 NAF and ultimately Stat6 (Hou et al, 1994;Kotanides and Reich, 1993;Quelle et al, 1995;Schindler et al, 1994).…”

Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer

“…Each of these is activated by specific stimuli. STAT6 was originally identified as a gamma-activated sequence binding protein in extracts derived from interleukin (IL)-4-treated cell lines (Kotanides and Reich, 1993;Hou et al, 1994;Schindler et al, 1994). Accordingly, IL-4 can specifically induce tyrosine phosphorylation of STAT6.…”

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).…”