Document Detail

Endocytic pathways and biological effects induced by UVB-dependent or ligand-dependent activation of the keratinocyte growth factor receptor.
MedLine Citation:
PMID:  16354720     Owner:  NLM     Status:  MEDLINE    
UVB exposure of epidermal cells is known to trigger early and late molecular pathways dependent on receptor tyrosine kinases and reactive oxygen species (ROS). We have recently reported that UVB irradiation induces tyrosine phosphorylation, kinase activation, and internalization of the receptor for the keratinocyte growth factor (KGFR), a paracrine mediator of epithelial growth, differentiation, and survival. Here we analyzed in more detail the UVB-induced endocytic pathway of KGFR and the role of KGFR activation and internalization in regulating UVB-promoted apoptosis and cell cycle arrest. Immunogold electron microscopy and confocal analysis revealed that the UVB-induced endocytosis of KGFR occurs through clathrin-coated pits and that the internalized receptors are sorted to the degradative route and reach the lysosomal compartment with a timing similar to that induced by their ligand KGF. Treatment with the anti-oxidant N-acetylcysteine inhibited KGFR endocytosis, suggesting that the receptor internalization is mediated by the intracellular production of ROS. The ligand-independent KGFR endocytic pathway induced by UVB requires receptor kinase activity and tyrosine phosphorylation and involves transient receptor ubiquitination. Inhibition of KGFR activity reduces both the KGF-mediated proliferative response and the UVB-promoted apoptotic cell death, indicating a different effect of ligand-induced and UVB-induced KGFR triggering. In addition, receptor internalization leads to protection from apoptosis caused by UVB exposure. Finally, we compared directly the behavior of KGFR with that of the epidermal growth factor receptor (EGFR) upon UVB exposure. Surprisingly, biochemical and immunofluorescence analysis showed that EGFR, differently from KGFR, does not undergo UVB-induced tyrosine phosphorylation and internalization. Taken together, our results suggest a differential role of KGFR and EGFR in the response of epidermal cells to UVB possibly because KGFR endocytosis could be crucial for attenuation of survival signals in the suprabasal layers of human skin.
Francesca Belleudi; Laura Leone; Laura Aimati; Maria Giovanna Stirparo; Giorgia Cardinali; Cinzia Marchese; Luigi Frati; Mauro Picardo; Maria Rosaria Torrisi
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-12-14
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  20     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-01     Completed Date:  2006-03-15     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  395-7     Citation Subset:  IM    
Dipartimento di Medicina Sperimentale e Patologia, Università di Roma La Sapienza, Rome, Italy.
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MeSH Terms
Cell Cycle
Clathrin / metabolism
Endocytosis / physiology*,  radiation effects*
Gene Expression Regulation
NIH 3T3 Cells
Phosphotyrosine / metabolism
Reactive Oxygen Species / metabolism
Receptor, Epidermal Growth Factor / metabolism
Receptor, Fibroblast Growth Factor, Type 2 / genetics,  metabolism*
Ultraviolet Rays*
Reg. No./Substance:
0/Clathrin; 0/Ligands; 0/Reactive Oxygen Species; 21820-51-9/Phosphotyrosine; EC 2.7.1.-/keratinocyte growth factor receptor; EC, Epidermal Growth Factor; EC, Fibroblast Growth Factor, Type 2

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