Journal
JOURNAL OF CELL SCIENCE
Volume 117, Issue 15, Pages 3189-3199Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.01190
Keywords
Rac1; macropinocytosis; heparan sulfate; growth factors; signaling
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Funding
- NHLBI NIH HHS [R01 HL065418-03, R01 HL065418-01A1, R01 HL065418, R01 HL065418-02, HL65418, HL63609, HL62289, HL53793] Funding Source: Medline
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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.
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