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

Yulia Ephstein, Patrick A. Singleton, Weiguo Chen, Lichun Wang, Ravi Salgia, Prasad Kanteti, Steven M. Dudek, Joe G.N. Garcia, Jeffrey R. Jacobson

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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 (1). 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.

Original languageEnglish (US)
Pages (from-to)2191-2200
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number4
DOIs
StatePublished - Jan 25 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ephstein, Y., Singleton, P. A., Chen, W., Wang, L., Salgia, R., Kanteti, P., Dudek, S. M., Garcia, J. G. N., & Jacobson, J. R. (2013). Critical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity. Journal of Biological Chemistry, 288(4), 2191-2200. https://doi.org/10.1074/jbc.M112.404780