Regulation of TPO-mediated c-Mpl receptor internalization and degradation. After TPO binding, clathrin-coated pits are formed through the interaction between the AP2 and Y₇₈RRL motif in the cytoplasmic tail of c-Mpl. The internalization process is regulated by Jak2 as well as SFKs activation (1). Following invagination and budding, (2) clathrin-coated vesicles are routed to endocytic pathways that direct the c-Mpl receptor to recycling and/or degradation (3). While Y₇₈RRL negatively regulates proliferation, Y₈RRL targets c-Mpl lysosomal degradation.