Mechanisms of EpoR down-regulation during Epo stimulation. Upon Epo binding, Jak2 (not represented) and the EpoR are tyrosine-phosphorylated, triggering intracellular signaling (Ia). At the cell surface, the receptor is ubiquitinated (II), allowing for recognition by the proteasome and degradation of the cytoplasmic tail (III). This degradation process removes the part of the receptor carrying all of the phosphorylated tyrosine residues of the intracellular domain, preventing further signal transduction. The cleaved receptor is then internalized and degraded in the lysosomes (IV). When Jak2 activation is prevented by the inhibitor AG490 (Ib), the receptor is neither phosphorylated nor ubiquitinated. Epo-EpoR complexes are still efficiently internalized, but no degradation occurs and the complexes recycle to the surface.