Adenovirus and protein kinase C have distinct molecular requirements for regulating epidermal growth factor receptor trafficking.
The ligand-activated tyrosine kinase receptor for epidermal growth factor (EGF) is down-regulated by an integral membrane protein coded for by the E3 early transcription unit of group C adenoviruses. The E3 protein appears to block recycling of constitutively internalized receptors, causing them instead to traffic to lysosomes where they are degraded. Expression of functional EGF receptors is also regulated by protein kinase C (PKC), which directly phosphorylates the EGF receptor at Thr-654. The goal of this study was to determine potential interactions between PKC and the E3 protein, since membrane-bound PKC activity is elevated by the adenovirus E1A protein. Our results show that although tumor promoters which activate PKC cause a coordinate induction of E3 protein synthesis and EGF receptor degradation, the E3 protein-induced pathway for receptor down-regulation functions independently of PKC and other kinases that are inhibited by staurosporine. This suggests that in contrast to other mechanisms that modulate receptor expression (i.e., ligand and PKC), the E3 protein is not regulated by phosphorylation but is constitutively active. We also report that adenovirus-mediated degradation is the preferred pathway in infected cells stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce receptor recycling.
Hoffman
B L
BL
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Takishima
K
K
Rosner
M R
MR
Carlin
C
C
D016475:3T3 Cells; D017503:Adenovirus E3 Proteins / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D017503:Adenovirus E3 Proteins; D000470:Alkaloids; D004247:DNA; D066246:ErbB Receptors; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate