Epidermal growth factor signaling pathway influences retinoid metabolism by reduction of retinyl ester hydrolase activities in normal and malignant keratinocytes.
The effects of EGFR signaling on retinol metabolism were evaluated in the squamous cell carcinoma cell lines defective in LRAT. In a 24-h incubation, the presence of EGF resulted in a 20-25% increase in retinyl ester accumulation. Assessment of retinol esterification and retinyl ester utilization (hydrolysis), in cell cultures and in cell homogenates, revealed that the increase in retinyl ester mass was the result of a reduction in retinyl ester hydrolysis. When grown in the absence of EGF, the cultures used about 40% of their retinyl esters, compared to about 21% in cultures grown with EGF. This effect of EGF was blocked by an EGF receptor-neutralizing antibody, an EGF receptor tyrosine-kinase inhibitor (PD153035), and a specific inhibitor of MEK kinase influencing the mitogen-activated protein kinase (MAPK) cascade (PD98059). Both transcription and translation were required, suggesting that signaling from the EGF receptor through the MAPK cascade controls the expression of modulators or inhibitors of the retinyl ester hydrolase(s). Thus EGFR signaling can alter the intracellular concentration of retinol by suppressing the access to the retinyl ester pool. Similar EGF effects were seen in cultures of normal keratinocytes.
Jurukovski
V
V
Department of Oral Biology and Pathology, State University of New York at Stony Brook, Stony Brook, NY 11794-8702, USA.
Simon
M
M
D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000378:metabolism
D012176:Retinoids; D014801:Vitamin A; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D002265:Carboxylic Ester Hydrolases; C022523:retinyl esterase