FIG 8.
Proposed model. AAK1 and GAK regulate two distinct steps in the HCV life cycle: entry and assembly. For HCV entry, AAK1 and GAK are critical for the regulation of HCV internalization. AAK1 and GAK phosphorylate the clathrin adaptor AP-2, and AAK1 phosphorylates the alternate adaptor NUMB. AP-2 and/or NUMB then collaborates with other endocytic factors, possibly also subjected to AAK1 and/or GAK regulation, to enhance endocytosis and/or recycling of EGFR and potentially an additional HCV coreceptor(s). In HCV assembly, AAK1 and GAK mediate HCV assembly independently of their role in HCV entry by regulating AP-2 binding to the HCV core protein on lipid droplets (LD) (76). Sunitinib inhibits AAK1, and erlotinib inhibits both EGFR and its regulator GAK, thereby disrupting both HCV entry and assembly. Numbers represent Kd values of binding of the drugs to the respective targets. Solid arrows represent target phosphorylations that we show are critical for HCV entry. Dashed lines represent protein-protein interactions. ER, endoplasmic reticulum.