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First published online June 28, 2004
doi: 10.1242/10.1242/jcs.01190
Research Article |
1 Angiogenesis Research Center and Section of Cardiology, Department of Medicine and Department of Pharmacology and Toxicology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
2 Department of Pathology, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756, USA
* Author for correspondence (e-mail: michael.simons{at}dartmouth.edu)
Accepted 26 February 2004
Full activity of fibroblast growth factors (FGFs) requires their internalization in addition to the interaction with cell surface receptors. Recent studies have suggested that the transmembrane proteoglycan syndecan-4 functions as a FGF2 receptor. In this study we investigated the molecular basis of syndecan endocytosis and its role in FGF2 internalization in endothelial cells. We found that syndecan-4 uptake, induced either by treatment with FGF2 or by antibody clustering, requires the integrity of plasma membrane lipid rafts for its initiation, occurs in a non-clathrin-, non-dynamin-dependent manner and involves Rac1, which is activated by syndecan-4 clustering. FGF2 was internalized in a complex with syndecan-4 in 70 kDa dextran-containing endocytic vesicles. FGF2 and syndecan-4 but not dextran endocytosis were blocked by the dominant negative Rac1 while amiloride and the dominant-negative Cdc42 blocked internalization of dextran in addition to FGF2 and syndecan-4. Taken together, these results demonstrate that FGF2 endocytosis requires syndecan-4 clustering-dependent activation of Rac1 and the intact CDC42-dependent macropinocytic pathway.
Key words: Rac1, Macropinocytosis, Heparan sulfate, Growth factors, Signaling
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