EPO activates the Cbl-Crk-C3G cascade. EPO activates multiple signaling cascades within hematopoietic cells. A critical adaptor protein necessary for Ras activation, Grb2, can bind constitutively to Cbl. However, the predominant complex following cytokine activation is the Cbl-Crk complex. The preferred complexes are indicated by bold lines and larger arrowheads. Dashed lines indicate associations that occur in vitro, based on immunoprecipitation experiments (ie, Grb2-Cbl and EPO-R-Crk), but may have lesser significance in vivo. It remains unclear how EPO-R couples to Cbl and whether EPO-R activates Rap1.