ShcA activation via Tyr573 of the IL-3/IL-5/GM-CSF receptor βc signals for IL-4 production in mouse primary basophils

Granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 signals are transmitted via the shared receptor subunit common β (βc). Earlier studies showed that distinct subdomains and tyrosine residues of βc are connected to specific downstream signaling pathways. However, as most of those pathways are for survival/proliferation, much remains to be learned about how βc transmits signals for effector functions. Here, by reconstituting primary βc-deficient basophils with βc mutants, we found that the tyrosine 573 of βc was required for recruiting and phosphorylating the adaptor ShcA and IL-4 production. Furthermore, dominant-negative ShcA and the ShcA inhibitor idebenone inhibited IL-4 production but not cell survival. These results provided further insight into how the functional pleiotropy of cytokines is supported by the structure of their receptors.