THE HUMAN-PAPILLOMAVIRUS TYPE-16 E5-PROTEIN MODULATES LIGAND-DEPENDENT ACTIVATION OF THE EGF RECEPTOR FAMILY IN THE HUMAN EPITHELIAL-CELL LINE HACAT

The E5 open reading frame of the human papillomavirus type 16 encodes a transmembrane protein associated with the Golgi, ER, and plasma memb ranes. We have analyzed the effect of E5 expression on the activation of the EGF receptor family. We find that expression of the EB-protein strongly enhances EC:FR activation in a Ligand-dependent manner. This activation takes place immediately after addition of ligand, demonstra ting that increased tyrosine phosphorylation cannot solely be due to a n impaired down regulation of the receptors, Furthermore, this activat ion is not a result of impaired activity of EGFR-specific phosphatases through the EB-protein, as demonstrated by using inhibitors specifica lly blocking EGFR activation. in addition, treatment with EGF results in an enhanced activation of the ErbB2 receptor in E5-expressing cells . This superactivation must be a result of heterodimer formation betwe en EGFR and ErbB2, since EGF is nota ligand for ErbB2. Finally, treatm ent of EB-expressing cells with HB-EGF shows no increased phosphorylat ion of the ErbB4 receptor, suggesting a specific effect of E5 on the a ctivation of the different members of the EGFR family. (C) 1998 Academ ic Press.