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Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments
Maria Grazia Lampugnani1,2,
Fabrizio Orsenigo1,
Maria Cristina Gagliani4,
Carlo Tacchetti4, , and
Elisabetta Dejana1,2,3
1 IFOM, Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology, 2 Mario Negri Institute for Pharmacological Research, and 3 Department of Biomolecular and Biotechnological Sciences, Faculty of Sciences, University of Milan, 20139 Milan, Italy 4 Department of Experimental Medicine, University of Genova, 16146 Genova, Italy
Correspondence to Elisabetta Dejana: elisabetta.dejana{at}ifom-ieo-campus.it
Abstract:
Receptor endocytosis is a fundamental step in controlling themagnitude, duration, and nature of cell signaling events. Confluentendothelial cells are contact inhibited in their growth andrespond poorly to the proliferative signals of vascular endothelialgrowth factor (VEGF). In a previous study, we found that theassociation of vascular endothelial cadherin (VEC) with VEGFreceptor (VEGFR) type 2 contributes to density-dependent growthinhibition (Lampugnani, G.M., A. Zanetti, M. Corada, T. Takahashi,G. Balconi, F. Breviario, F. Orsenigo, A. Cattelino, R. Kemler,T.O. Daniel, and E. Dejana. 2003. J. Cell Biol. 161:793–804).In the present study, we describe the mechanism through whichVEC reduces VEGFR-2 signaling. We found that VEGF induces theclathrin-dependent internalization of VEGFR-2. When VEC is absentor not engaged at junctions, VEGFR-2 is internalized more rapidlyand remains in endosomal compartments for a longer time. Internalizationdoes not terminate its signaling; instead, the internalizedreceptor is phosphorylated, codistributes with active phospholipaseC–, and activates p44/42 mitogen-activated protein kinasephosphorylation and cell proliferation. Inhibition of VEGFR-2internalization reestablishes the contact inhibition of cellgrowth, whereas silencing the junction-associated density-enhancedphosphatase-1/CD148 phosphatase restores VEGFR-2 internalizationand signaling. Thus, VEC limits cell proliferation by retainingVEGFR-2 at the membrane and preventing its internalization intosignaling compartments.
Abbreviations used in this paper: EEA-1, early endosomal antigen-1;DEP-1, density-enhanced phosphatase-1; GSH, glutathione; HUVEC,human umbilical vein endothelial cell; PY, phosphotyrosine;VEC, vascular endothelial cadherin; VEGFR, VEGF receptor.
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, and activates p44/42 mitogen-activated protein kinase phosphorylation and cell proliferation. Inhibition of VEGFR-2 internalization reestablishes the contact inhibition of cell growth, whereas silencing the junction-associated density-enhanced phosphatase-1/CD148 phosphatase restores VEGFR-2 internalization and signaling. Thus, VEC limits cell proliferation by retaining VEGFR-2 at the membrane and preventing its internalization into signaling compartments. 
