Caveolin-1 is required for signaling and membrane targeting of EphB1 receptor tyrosine kinase.
Eph receptor tyrosine kinases are key players during the development of the embryonic vasculature; however, their role and regulation in adult angiogenesis remain to be defined. Caveolae are flask-shaped invaginations of the cell membrane; their major structural protein, caveolin-1, has been shown to regulate signaling molecules localized in these micro-domains. The interaction of caveolin-1 with several of these proteins is mediated by the binding of its scaffolding domain to a region containing hydrophobic amino acids within these proteins. The presence of such a motif within the EphB1 kinase domain prompted us to investigate the caveolar localization and regulation of EphB1 by caveolin-1. We report that EphB1 receptors are localized in caveolae, and directly interact with caveolin-1 upon ligand stimulation. This interaction, as well as EphB1-mediated activation of extracellular-signal-regulated kinase (ERK), was abrogated by overexpression of a caveolin-1 mutant lacking a functional scaffolding domain. Interaction between Ephs and caveolin-1 is not restricted to the B-subclass of receptors, since we show that EphA2 also interacts with caveolin-1. Furthermore, we demonstrate that the caveolin-binding motif within the kinase domain of EphB1 is primordial for its correct membrane targeting. Taken together, our findings establish caveolin-1 as an important regulator of downstream signaling and membrane targeting of EphB1.
Vihanto
Meri M
MM
Department of Nephrology and Hypertension, Inselspital, University of Bern, Switzerland.
Vindis
Cecile
C
Djonov
Valentin
V
Cerretti
Douglas P
DP
Huynh-Do
Uyen
U
D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D051242:Caveolin 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000494:pharmacology; D006224:Cricetinae; D036388:Ephrin-B2 / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D036104:Receptor, EphA2 / Q000378:metabolism; D036225:Receptor, EphB1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D051242:Caveolin 1; D036388:Ephrin-B2; D002784:Cholesterol; D036104:Receptor, EphA2; D036225:Receptor, EphB1; D048049:Extracellular Signal-Regulated MAP Kinases