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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Published in:The Journal of cell biology Vol. 174; no. 4; p. 593
Main Authors: Lampugnani, Maria Grazia, Orsenigo, Fabrizio, Gagliani, Maria Cristina, Tacchetti, Carlo, Dejana, Elisabetta
Format: Journal Article
Language:English
Published: United States 14.08.2006
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:0021-9525
DOI:10.1083/jcb.200602080