Document Detail

Activation of vascular endothelial growth factor receptor 2 in a cellular model of loricrin keratoderma.
MedLine Citation:
PMID:  20236940     Owner:  NLM     Status:  MEDLINE    
Loricrin is a major constituent of the epidermal cornified cell envelope. Recently, heterozygous loricrin gene mutations have been identified in two dominantly inherited skin diseases, Vohwinkel syndrome with ichthyosis and progressive symmetric erythrokeratoderma, collectively termed loricrin keratoderma. We generated stable HaCaT cell lines that express wild-type (WT) loricrin and a mutant form found in Vohwinkel syndrome with ichthyosis, using an ecdysone-inducible promoter system. The cells expressing the mutant loricrin grew more rapidly than those expressing WT loricrin after induction for 5 days. Confocal immunofluorescence microscopy revealed that phospho-Akt occurred in the nucleolus where the mutant loricrin was also located. The level of activity of Akt kinase was about nine times higher in cells with the mutant than in those with WT loricrin. ERK1/2, the epidermal growth factor receptor, vascular endothelial growth factor (VEGF) receptor 2 and Stat3 were all phosphorylated in cells with the mutant loricrin. The docking proteins, Gab1 and c-Cbl, were also tyrosine-phosphorylated in these cells. Furthermore, chromatin immunoprecipitation assays showed that Stat3 protein bound to the VEGF promoter in cells with the mutant. Thus, this study suggests that VEGF release and the subsequent activation of VEGF receptor 2 link loricrin gene mutations to rapid cell proliferation in a cellular model of loricrin keratoderma.
Kozo Yoneda; Toshio Demitsu; Kozo Nakai; Tetsuya Moriue; Wataru Ogawa; Junsuke Igarashi; Hiroaki Kosaka; Yasuo Kubota
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-17     Completed Date:  2010-06-14     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16184-94     Citation Subset:  IM    
Department of Dermatology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
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MeSH Terms
Adaptor Proteins, Signal Transducing / genetics,  metabolism
Cell Line, Transformed
Cell Nucleus / metabolism*,  pathology
Cell Proliferation
Epidermis / metabolism,  pathology
Membrane Proteins / genetics,  metabolism*
Mitogen-Activated Protein Kinase 3 / genetics,  metabolism
Models, Biological*
Phosphorylation / genetics
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-cbl / genetics,  metabolism
STAT3 Transcription Factor / genetics,  metabolism
Skin Diseases, Genetic / genetics,  metabolism*,  pathology
Vascular Endothelial Growth Factor A / genetics,  metabolism
Vascular Endothelial Growth Factor Receptor-2 / genetics,  metabolism*
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/GAB1 protein, human; 0/Membrane Proteins; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; 0/loricrin; EC Endothelial Growth Factor Receptor-2; EC Proteins c-akt; EC Protein Kinase 3; EC 6.3.2.-/CBL protein, human; EC 6.3.2.-/Proto-Oncogene Proteins c-cbl

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