Published online 7 August 2006. doi:10.1083/jcb.1744iti4
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 4, 475-475
Cadherin stops receptor endocytosis
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Internalization of VEGFR-2 (green) into early endosomes (red) is blocked by VE–Cadherin.
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Acadherin that holds together vascular cells also keeps a growth factor receptor fixed in place, say Lampugnani et al., on page 593. The cadherin's tug keeps the receptor on the surface, where it cannot induce the cell to proliferate.
Proliferation is fine when there is room to grow, but endothelial cells prevent overcrowding by becoming insensitive to growth factors such as VEGF. This insensitivity requires an association between the VEGF receptor type 2 (VEGFR-2) and a cell–cell junction adhesion molecule called VE–cadherin. In the new work, the authors discover that this connection prevents VEGFR-2 internalization.
In disperse cells, the authors found, VEGF-bound receptor was phosphorylated and internalized into early endosomes via clathrin-mediated endocytosis. Although internalization often ends a receptor's signaling abilities (by leading to receptor recycling or degradation), several receptors have been recently shown to be most active from within early endosomes, where they are protected from degradation. Indeed, endosomal VEGFR-2 turned on proliferation-inducing MAPK pathways.
VEGFR-2 endocytosis was prevented, however, when the receptor was associated with VE–cadherin, which may be a mechanical obstacle to the clathrin machinery. Left on the surface, VEGFR-2 was vulnerable to dephosphorylation—and thus deactivation—by the DEP-1 phosphatase. Dephosphorylation might also further prevent internalization.
Before forming new blood vessels, endothelial cells dismantle their cell–cell junctions by down-regulating VE–cadherin, thus freeing VEGFR-2 from the grips of VE–cadherin and allowing its endocytosis in response to growth factors. Blocking this internalization step with drugs might be an alternative way to prevent new vessel formation, which is necessary for tumor growth. 
Nicole LeBrasseur
lebrasn{at}rockefeller.edu
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