Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments

Receptor endocytosis is a fundamental step in controlling the magnitude, duration, and nature of cell signaling events. Confluent endothelial cells are contact inhibited in their growth and respond poorly to the proliferative signals of vascular endothelial growth factor (VEGF). In a previous study,...

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Vydáno v:	The Journal of cell biology Ročník 174; číslo 4; s. 593
Hlavní autoři:	Lampugnani, Maria Grazia, Orsenigo, Fabrizio, Gagliani, Maria Cristina, Tacchetti, Carlo, Dejana, Elisabetta
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 14.08.2006
Témata:	Antigens, CD - metabolism Cadherins - metabolism Cell Compartmentation - drug effects Cell Compartmentation - physiology Cell Membrane - metabolism Cell Proliferation - drug effects Cells, Cultured Endocytosis - drug effects Endocytosis - physiology Endothelial Cells - metabolism Endothelial Cells - ultrastructure Enzyme Activation - drug effects Enzyme Activation - physiology Humans Intracellular Membranes - metabolism Intracellular Membranes - ultrastructure Mitogen-Activated Protein Kinase 3 - metabolism Phospholipase C gamma - metabolism Phosphorylation Protein Phosphatase 1 Protein Tyrosine Phosphatases - metabolism Receptor-Like Protein Tyrosine Phosphatases, Class 3 Signal Transduction - drug effects Signal Transduction - physiology Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor A - pharmacology Vascular Endothelial Growth Factor Receptor-2 - agonists Vascular Endothelial Growth Factor Receptor-2 - metabolism
ISSN:	0021-9525
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Shrnutí:	Receptor endocytosis is a fundamental step in controlling the magnitude, duration, and nature of cell signaling events. Confluent endothelial cells are contact inhibited in their growth and respond poorly to the proliferative signals of vascular endothelial growth factor (VEGF). In a previous study, we found that the association of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to density-dependent growth inhibition (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 which VEC reduces VEGFR-2 signaling. We found that VEGF induces the clathrin-dependent internalization of VEGFR-2. When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly and remains in endosomal compartments for a longer time. Internalization does not terminate its signaling; instead, the internalized receptor is phosphorylated, codistributes with active phospholipase C-gamma, 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9525
DOI:	10.1083/jcb.200602080