The cytoplasmic tail of heparin-binding EGF-like growth factor regulates bidirectional intracellular trafficking between the plasma membrane and ER

Heparin-binding epidermal growth factor (EGF)- like growth factor (HB-EGF) is synthesized in the ER, transported along the exocytic pathway, and expressed on the plasma membrane as a type I transmembrane protein. Upon extracellular stimulation, HB-EGF, either proHB-EGF or the shed form HB-EGF-CTF, undergoes endocytosis and is then transported retrogradely to the ER. In this study, we showed the essential contribution of the short cytoplasmic tail of HB-EGF (HB-EGF-cyto) to the bidirectional intracellular trafficking between the ER and plasma membrane and revealed several critical amino acids residues that are responsible for internalization from the plasma membrane and ER targeting. We suggest that these anterograde and retrograde sorting signals within HB-EGF-cyto are strictly regulated by protein modification and conformation.

▸ The cytoplasmic tail of HB-EGF contributes to bidirectional intracellular trafficking. ▸ The carboxyl-terminal five amino acids are indispensable for internalization. ▸ Amino acids S207 and K201 play essential roles in retrograde transport to the ER. ▸ Sorting signals in HB-EGF are regulated by protein modification and conformation. ▸ The extracellular domain of proHB-EGF is not required for intracellular trafficking.