Critical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity.

TitleCritical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity.
Publication TypeJournal Article
Year of Publication2013
AuthorsEphstein Y, Singleton PA, Chen W, Wang L, Salgia R, Kanteti P, Dudek SM, Garcia JGN, Jacobson JR
JournalJ Biol Chem
Date Published2013 Jan 25
ISSN Number1083-351X
KeywordsCell Membrane, Electrophysiology, Endothelial Cells, Hepatocyte Growth Factor, Humans, Integrin beta4, Lung, Membrane Microdomains, Microcirculation, Models, Biological, Proto-Oncogene Proteins c-met, rac1 GTP-Binding Protein, Receptors, Lysosphingolipid, RNA, Small Interfering, Threonine, Transcriptional Activation, Tyrosine

<p>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.</p>

Alternate JournalJ. Biol. Chem.
PubMed ID23212923
PubMed Central IDPMC3554892
Grant ListR01 HL095723 / HL / NHLBI NIH HHS / United States
R01 HL096887 / HL / NHLBI NIH HHS / United States