The granulocyte-macrophage colonystimulating factor (GM-CSF)/interleukin (IL)-3/IL-5 receptor family regulates the production and function of myeloid cells. These cytokines signal through receptor complexes that consist of unique ligandbinding ␣-chains and common signaling -chains. IL-5 is distinct from IL-3 and GM-CSF in its capacity to induce eosinophil development, however, the molecular mechanisms that generate functional diversity within this receptor family are mostly unknown. Here, we characterized the selective IL-5R␣-binding adapter protein syntenin in IL-5R function. Syntenin and IL-5R␣ colocalize at the plasma membrane and in early endosomal compartments. Manipulation of syntenin expression by ectopic expression or knockdown selectively modulated IL-5R but not GM-CSF receptor signaling, and severely affected IL-5-induced eosinophil differentiation from primary human CD34 ؉ hematopoietic progenitor cells. We found syntenin upregulated during eosinophilopoiesis but down-regulated during neutropoiesis. Syntenin forms complexes with multiple IL-5R␣ chains, suggesting that synteninenhanced IL-5R output may result from stabilization of an IL-5-induced oligomeric receptor complex. These data demonstrate that cytokine-specific functions can be transduced by unique receptor ␣-chain-associating adapter proteins. (Blood. 2009;114:3917-3927)
IntroductionLeukocyte functions are regulated by intracellular mechanisms that constantly integrate environmental signals. Cytokines and their receptors are key molecules in leukocyte communication that regulate hematopoiesis and immune responses. 1 Cytokine receptors have been classified on the shared use of common receptor components such as the common -chain (c) for the granulocytemacrophage colony-stimulating factor receptor (GM-CSFR) family. 2 Tightly regulated and complex signaling networks have evolved to ensure robust cellular output of cytokine-mediated signaling input. Adapter and scaffold proteins play a decisive role in these networks by regulating the kinetics and specificity of signal transduction pathways. 3 These proteins consist of multiple protein interaction domains that lack enzymatic activity, and modulate the composition of protein complexes and thus which protein substrates are favorably targeted. Adapter molecules may allow the induction of receptor-specific signaling pathways, and cellular functions, however until now there are few examples.IL-3, IL-5, and GM-CSF are important regulators of myeloid cell differentiation and leukocyte function. 4 These cytokines bind to unique ␣-chains, and then recruit a common -chain (c) to form high-affinity receptors. Receptor activation induces overlapping signaling pathways that depend on both ␣ and c which are preassociated with Janus kinases (JAKs) that activate signal transducer and activators of transcription (STAT). 4,5 Other shared signaling pathways include the phosphoinositol-3 kinase (PI-3K)/ protein kinase B pathway (PKB/c-Akt) that is crucial for cellular survival, and mitogen-activated protein ki...