The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1).
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Kobayashi S, Sawano A, Nojima Y, Shibuya M, Maru Y
The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1).
FASEB J. 2004 May;18(7):929-31. Epub 2004 Mar 4.
- PubMed ID
- 15001553 [ View in PubMed]
- Abstract
Vascular endothelial growth factor (VEGF) and its receptors are key regulators of angiogenesis and are potential targets in cancer therapy. Here we report the down-regulation of activated VEGF receptor (VEGFR)-1/Flt-1 by endocytosis and proteolytic degradation. VEGF stimulation induced a ternary complex of Flt-1, c-Cbl, and CD2AP. Substitution of tyrosine 1333 in Flt-1 with phenylalanine (Y1333F) impaired its binding to c-Cbl. In a transient expression system, VEGF stimulated colocalization of Flt-1, CD2AP, and c-Cbl in endocytic vesicles. This colocalization was significantly impaired by an inhibitor of VEGFR kinase SU5416, the Y1333F mutation in Flt-1, or by a dominant negative form of CD2AP. In Flt-1-overexpressing NIH3T3 cells, expression of the wild-type CD2AP enhanced VEGF-stimulated internalization as well as ubiquitination of Flt-1 whereas that of a mutated form of either CD2AP or c-Cbl failed to do so. These results suggest that the c-Cbl/CD2AP complex binds to activated Flt-1 and plays a crucial role in its endocytosis and subsequent degradation.