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

We have investigated mechanisms and consequences of STAT5 activation throug h the human IL-4 receptor (IL-4R). By functionally expressing receptor muta nts 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-ind uced STAT5 activity. However, disruption of a membrane-proximal proline-ric h sequence motif ('box1') in either subunit of the bipartite IL-4R abolishe d not only ligand-induced tyrosine phosphorylation of Janus kinases JAK1 an d JAK3, but also IL-4-triggered activation of STAT5 and concomitant cell pr oliferation. A dominant-negative version of STAT5b, but not of STAT5a, inte rfered with IL-4-induced DNA synthesis in Ba/F3 cells, suggesting an involv ement of STAT5b in the control of cell proliferation through IL-4R. Reporte r gene experiments finally showed that transcription from promoters of STAT 5 target genes can be specifically induced by challenging cells with IL-4, and that both STAT5a and STAT5b can contribute to IL-4-triggered transcript ional control.