AbstractRecent studies have suggested that the membrane proximal region of the cytoplasmic domain of the erythropoietin receptor and other members of the cytokine receptor superfamily may be required for signal transduction. Expression of several deletion mutants of the erythropoietin receptor in Ba/F3 cells showed that a region with homology to the interleukin-2 receptorβ-chain which includes Box 2 is not essential for erythropoietin-dependent cell proliferation. However, a region between Box 1 and Box 2 contains essential residues for proliferative response. Expression of mutant receptors was confirmed by reverse transcriptase-PCR analysis and by Western blotting, which also showed no evidence for expression of endogenous wild-type receptor. These findings are in direct conflict with previously reported mutagenesis studies of the erythropoietin receptor suggesting that mitogenesis may be channelled through more than one pathway depending on the complement of signaling molecules expressed in the cell.