Functional cross-talk between cytokine receptors revealed by activating mutations in the extracellular domain of the β-subunit of the GM-CSF receptor

Several reports have suggested an interaction between the erythropoietin receptor (EpoR) and the shared signaling subunit (hβ_c) of the human granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 receptors, although the functional consequences of this interaction are unclear. We previously showed that in vivo expression of constitutively active extracellular (EC) mutants of hβ_c induces erythrocytosis and Epo independence of erythroid colony-forming units (CFU-E). This occurs despite an apparent requirement of these mutants for the GM-CSF receptor α-subunit (GMRα), which is not expressed in CFU-E. Here, we show that coexpression of hβ_c EC mutants and EpoR in BaF-B03 cells, which lack GMRα, results in factor-independent proliferation and JAK2 activation. Mutant receptors that cannot activate JAK2 fail to produce a functional interaction. As there is no detectable phosphorylation of hβ_c on intracellular tyrosine residues, EpoR displays constitutive tyrosine phosphorylation. These observations suggest that JAK2 activation mediates cross-talk between EC mutants of hβ_c and EpoR. The implications of these data are discussed as are our findings that activated hβ_c mutants can functionally interact with certain other cytokine receptors.