Activation of STAT5 by IL-4 relies on Janus kinase function but not on receptor tyrosine phosphorylation, and can contribute to both cell proliferation and gene regulation

Abstract

We have investigated mechanisms and consequences of STAT5 activation through the human IL-4 receptor (IL-4R). By functionally expressing receptor mutants in the murine pro-B cell line Ba/F3, we could show that phosphorylated tyrosine residues within the IL-4R alpha chain are dispensable for IL-4-induced STAT5 activity. However, disruption of a membrane-proximal proline-rich sequence motif ('box1') in either subunit of the bipartite IL-4R abolished not only ligand-induced tyrosine phosphorylation of Janus kinases JAK1 and JAK3, but also IL-4-triggered activation of STAT5 and concomitant cell proliferation. A dominant-negative version of STAT5b, but not of STAT5a, interfered with IL-4-induced DNA synthesis in Ba/F3 cells, suggesting an involvement of STAT5b in the control of cell proliferation through IL-4R. Reporter gene experiments finally showed that transcription from promoters of STAT5 target genes can be specifically induced by challenging cells with IL-4, and that both STAT5a and STAT5b can contribute to IL-4-triggered transcriptional control.

Interleukin 2 plays a central role in Th2 differentiation

“…In agreement with a recent study (19), we showed that in vitro priming for IL-4 production is impaired in Stat5a Ϫ/Ϫ T cells under ''neutral'' conditions. IL-4 may cause Stat5 phosphorylation (20), but its magnitude is modest (see Fig. 3b), consistent with the inability of IL-4 to replace IL-2 function.…”

Uncoupling of Proliferation and Stat5 Activation in Thymic Stromal Lymphopoietin-Mediated Signal Transduction

“…There are many reports of cytokine receptor mutations that block both Stat activation and proliferation (18,23,26,(32)(33)(34), including the Box1 mutations described in this work. There are also reports of cytokine receptor mutations that eliminate Stat activation without affecting cell proliferation, including erythropoietin-and IL-2-induced Stat5 activation (18), and thrombopoietininduced Stat1, -3, and -5 activation (35).…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…IL-4 has also been reported to activate Stat5 in lymphocytes; however, this activation appears not to depend on the phospho-tyrosine docking sites in IL4Ra but rather it may instead depend on interaction with a JAK kinase (Friedrich et al, 1999) or g c (Lischke et al, 1998). It therefore likely represents additional mechanism(s) by which IL-2 family cytokines activate Stat5 proteins.…”