Cytokine receptors consist of multiple subunits, which are often shared between different receptors, resulting in the functional redundancy sometimes observed between cytokines. The interleukin 5 (IL-5) receptor consists of an IL-5–specific α-subunit (IL-5Rα) and a signal-transducing β-subunit (βc) shared with the IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors. In this study, we sought to find a role for the cytoplasmic domain of IL-5Rα. We show that syntenin, a protein containing PSD-95/Discs large/zO-1 (PDZ) domains, associates with the cytoplasmic tail of the IL-5Rα. Syntenin was found to directly associate with the transcription factor Sox4. Association of syntenin with IL-5Rα was required for IL-5–mediated activation of Sox4. These studies identify a mechanism of transcriptional activation by cytokine-specific receptor subunits.