Cbl knockdown results in hypersensitivity to Epo. (A) BaF3 cells expressing HA-EpoR and either Cbl shRNA or control shRNA were grown in RPMI media containing 2% FBS with different concentrations of Epo. Cell growth was measured using MTT assays. Cells grew similarly in control media containing no Epo but IL-3 (WEHI media) and 10% FBS. *P < .05, **P < .005. (B) Expression of Cbl shRNA but not control shRNA in primary Ter119^– erythroid progenitors resulted in Epo hypersensitivity in IMDM media containing 2% FBS and different concentrations of Epo. Cells grew similarly in control expansion media (2 U/mL Epo). *P < .05, **P < .005. (C) A working model of p85-mediated EpoR internalization. Epo stimulates binding of p85 to both Cbl and the EpoR through its SH2 domains, possibly forming a tripartite complex. Epo also induces Cbl ubiquitination of p85, which in turn recruits epsin-1 through its UIMs to further enlist the endocytic machinery for EpoR internalization (details are described in the Discussion).