The RAS guanine nucleotide exchange factors SOS1 and VAV1 bind indirectly to the phosphorylated EPOR via CRKL, SHC1, and GRB2 (Miura et al. 1994, Hanazono et al. 1996, Odai et al. 1997, Arai et al. 2001, reviewed in Kuhrt et al. 2015) . The phosphorylated cytoplasmic domain of EPOR binds CRKL, which is then phosphorylated (Arai et al. 2001). Phosphorylated CRKL binds SHC1, which is then phosphorylated and binds either GRB2:SOS1 (Barber et al. 1997) or GRB2:VAV1 (Hanazono et al. 1996). SOS1 and phosphorylated VAV1 catalyze the exchange of GDP for GTP bound to RAS, that is, RAS:GDP is converted to RAS:GTP.