The Na+-Taurocholate Cotransporting Polypeptide Traffics with the Epidermal Growth Factor Receptor

Na+-taurocholate cotransporting polypeptide (ntcp) mediates uptake of bile acids as well as serving as the receptor for hepatitis B virus in human liver. Previous studies showed that ntcp traffics on microtubules between the cell surface and endocytic vesicles. Specific inhibition of protein kinase C (PKC) resulted in loss of microtubule-based motility of these vesicles in vitro and in living cells. The aim of this study was to characterize the PKC target. Incubation of ntcp-containing endocytic vesicles with -P-32-ATP revealed a 180 kDa phosphoglycoprotein that was identified as the epidermal growth factor (EGF) receptor (EGFR). Surface biotinylation of HuH7 cells expressing green fluorescent protein (GFP)-ntcp revealed substantially reduced trafficking of ntcp to the cell surface with EGFR knockdown. Microtubule-based motility of ntcp-containing endocytic vesicles was also significantly reduced when they were not associated with EGFR. ntcp was also found to undergo cellular redistribution upon stimulation of cells with EGF, consistent with a model in which ntcp and EGF-EGFR internalize into common endocytic vesicles from which they segregate, trafficking EGF-EGFR to lysosomes and recycling ntcp to the plasma membrane. EGF regulation of ntcp trafficking may play a heretofore unanticipated role in subcellular targeting of ntcp ligands such as hepatitis B.