Document Detail

Critical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity.
MedLine Citation:
PMID:  23212923     Owner:  NLM     Status:  MEDLINE    
Vascular endothelial cell (EC) barrier integrity is critical to vessel homeostasis whereas barrier dysfunction is a key feature of inflammatory disorders and tumor angiogenesis. We previously reported that hepatocyte growth factor (HGF)-mediated increases in EC barrier integrity are signaled through a dynamic complex present in lipid rafts involving its receptor, c-Met. We extended these observations to confirm that S1PR1 (sphingosine 1-phosphate receptor 1) and integrin β4 (ITGB4) are essential participants in HGF-induced EC barrier enhancement. Immunoprecipitation experiments demonstrated HGF-mediated recruitment of c-Met, ITGB4 and S1PR1 to caveolin-enriched lipid rafts in human lung EC with direct interactions of c-Met with both S1PR1 and ITGB4 accompanied by c-Met-dependent S1PR1 and ITGB4 transactivation. Reduced S1PR1 expression (siRNA) attenuated both ITGB4 and Rac1 activation as well as c-Met/ITGB4 interaction and resulted in decreased transendothelial electrical resistance. Furthermore, reduced ITGB4 expression attenuated HGF-induced c-Met activation, c-Met/S1PR1 interaction, and effected decreases in S1P- and HGF-induced EC barrier enhancement. Finally, the c-Met inhibitor, XL880, suppressed HGF-induced c-Met activation as well as S1PR1 and ITGB4 transactivation. These results support a critical role for S1PR1 and ITGB4 transactivation as rate-limiting events in the transduction of HGF signals via a dynamic c-Met complex resulting in enhanced EC barrier integrity.
Yulia Ephstein; Patrick A Singleton; Weiguo Chen; Lichun Wang; Ravi Salgia; Prasad Kanteti; Steven M Dudek; Joe G N Garcia; Jeffrey R Jacobson
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Publication Detail:
Type:  Journal Article     Date:  2012-12-04
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-04-02     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2191-200     Citation Subset:  IM    
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MeSH Terms
Cell Membrane / metabolism
Endothelial Cells / cytology*
Hepatocyte Growth Factor / metabolism*
Integrin beta4 / metabolism*
Lung / metabolism
Membrane Microdomains / chemistry,  metabolism
Models, Biological
Proto-Oncogene Proteins c-met / metabolism*
RNA, Small Interfering / metabolism
Receptors, Lysosphingolipid / metabolism*
Threonine / chemistry
Transcriptional Activation
Tyrosine / chemistry
rac1 GTP-Binding Protein / metabolism
Grant Support
Reg. No./Substance:
0/ITGB4 protein, human; 0/Integrin beta4; 0/RAC1 protein, human; 0/RNA, Small Interfering; 0/Receptors, Lysosphingolipid; 0/S1PR1 protein, human; 2ZD004190S/Threonine; 42HK56048U/Tyrosine; 67256-21-7/Hepatocyte Growth Factor; EC Proteins c-met; EC GTP-Binding Protein

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