Upon binding EPO, the EPOR dimer changes conformation, resulting in activation of JAK2 associated with box 1 and box 2 of the cytoplasmic domain of each EPOR (inferred from mouse homologs). One JAK2 transphosphorylates 12 tyrosine residues of the other JAK2 thereby activating JAK2 to phosphorylate EPOR and other substrates (Arcasoy et al. 1999, Watowich et al. 1999, Erickson-Miller et al. 2000, and inferred from mouse homologs).