Ultraviolet irradiation-induces epidermal growth factor receptor (EGFR) nuclear translocation in human keratinocytes.
Epidermal growth factor receptor (EGFR) plays a critical role in mediating ultraviolet (UV) irradiation-induced signal transduction and gene expression in human keratinocytes. EGFR activation results from increased phosphorylation on specific tyrosine residues in the C-terminal intracellular domain. It has recently been reported that following growth factor stimulation EGFR translocates from the surface membrane to the nucleus, where it may directly regulate gene transcription. We have investigated the ability of UV irradiation to induce EGFR nuclear translocation in human primary and HaCaT keratinocytes. UV irradiation caused rapid nuclear translocation of EGFR. Significant accumulation of EGFR in the nucleus was observed within 15 min after UV irradiation exposure. Maximal translocation occurred at 30 min post-UV irradiation, and resulted in a 10-fold increase in EGFR in the nucleus, as determined by Western blot analysis of nuclear extracts and confirmed by immunofluorescence. Inhibition of nuclear export by Leptomycin B did not alter UV irradiation-induced nuclear accumulation. EGFR tyrosine kinase inhibitor (PD169540) reduced UV irradiation-induced EGFR nuclear translocation 50%. Mutation of either tyrosine 1148 or tyrosine 1173 reduced nuclear translocation 70%, while mutation of tyrosine 1068 was without effect. In addition, over-expression of receptor type protein tyrosine phosphatase-kappa (RPTP-kappa), which specifically dephosphorylates EGFR tyrosines, decreased UV irradiation-induced EGFR nuclear translocation in human keratinocytes. These data demonstrate that UV irradiation stimulates rapid EGFR nuclear translocation, which is dependent on phosphorylation of specific EGFR tyrosine residues. EGFR nuclear translocation may act in concert with conventional signaling pathways to mediate UV irradiation-induced responses in human keratinocytes.
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Yiru
Y
Xu
Yuan
Y
Shao
Jin
J
Zhou
John J
JJ
Voorhees
Gary J
GJ
Fisher
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D016466:CHO Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects*; D006224:Cricetinae; D003412:Cricetulus; D004307:Dose-Response Relationship, Radiation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects*; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays
D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; C512478:EGFR protein, human; D066246:ErbB Receptors; C489852:PTPRK protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2