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 membranes. We have analyzed the effect of E5 expression on the activation of the EGF receptor family. We find that expression of the E5-protein strongly enhances EGFR activation in a ligand-dependent manner. This activation takes place immediately after addition of ligand, demonstrating that increased tyrosine phosphorylation cannot solely be due to an impaired downregulation of the receptors. Furthermore, this activation is not a result of impaired activity of EGFR-specific phosphatase through the E5-protein, as demonstrated by using inhibitors specifically 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 between EGFR and ErbB2, since EGF is not a ligand for ErbB2. Finally, treatment of E5-expressing cells with HB-EGF shows no increased phosphorylation of the ErbB4 receptor, suggesting a specific effect of E5 on the activation of the different members of the EGFR family.
Crusius
K
K
Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
Auvinen
E
E
Steuer
B
B
Gaissert
H
H
Alonso
A
A
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008024:Ligands; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000235:genetics; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D000086082:Viroporin Proteins
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008024:Ligands; D009856:Oncogene Proteins, Viral; D010744:Phosphoric Monoester Hydrolases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C587689:ERBB4 protein, human