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 assocn. of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to d.-dependent growth inhibition. 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-g, 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-assocd. d.-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. [on SciFinder (R)]

Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments / Maria Grazia Lampugnani, Fabrizio Orsenigo, Maria Cristina Gagliani, Carlo Tacchetti, Elisabetta Dejana. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 174:4(2006), pp. 593-604.

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

Elisabetta Dejana
2006

Abstract

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 assocn. of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to d.-dependent growth inhibition. 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-g, 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-assocd. d.-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. [on SciFinder (R)]
Cadherins Role: BSU (Biological study, unclassified), BIOL (Biological study) (5; vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments); Biological transport (internalization; vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments); Vascular endothelial growth factor receptors Role: BSU (Biological study, unclassified), BIOL (Biological study) (type VEGFR-2; vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments); Endothelium (umbilical venous; vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments in human umbilical vein endothelium); Vein (umbilical, endothelium; vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments in human umbilical vein endothelium); Cell junction; Cell proliferation; Phosphorylation; Signal transduction (vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments); Clathrin Role: BSU (Biological study, unclassified), BIOL (Biological study) (vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments); Human (vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments in human umbilical vein endothelium)
Settore MED/04 - Patologia Generale
2006
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/28688
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