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The secretion of VEGF165 involves a shedding step from the cell surface
Author(s) -
GuzmanHernandez Maria Luisa,
Potter Gael,
Kim Yeun Ju,
Kiss Jozsef Z.,
Balla Tamas
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.591.4
Subject(s) - secretion , microbiology and biotechnology , endoplasmic reticulum , exocytosis , golgi apparatus , angiogenesis , intracellular , secretory pathway , vascular endothelial growth factor , cytoplasm , chemistry , gtpase , biology , vegf receptors , biochemistry , cancer research
VEGF165 is the major isoform of vascular endothelial growth factor (VEGF) that controls physiological and pathological angiogenesis. While the functional roles of VEGF165 have been extensively studied, its intracellular trafficking and mode of secretion remain largely unknown. In previous studies we reported on the trafficking steps of VEGF165 fused with GFP. We showed that like its native form, VEGF165‐GFP forms dimers and gets glycosylated and exerts biological activity tested on HUVEC cells. VEGF165‐GFP secretion follows the endoplasmic reticulum‐Golgi pathway as indicated by the ability of GTP‐locked Sar1 and Arf1 GTPases to completely prevent VEGF secretion. VEGF secretion is relatively insensitive to temperature drops from 37 to 19 ºC and is stimulated by cytoplasmic Ca2+ increases and PKC activators or inhibitors of the mTORC1 pathway. Exocytosis of VEGF165 requires PIP2 at the plasma membrane and a significant fraction of the externalized VEGF remains associated with the plasma membrane in discrete patchy areas. Here we show that EM analysis reveals that a substantial fraction of VEGF is shedding from the cell surface together with matrix components. Overall our results for the first time identify important steps in the trafficking and secretion mechanism of VEGF providing new information that can be explored to devise new strategies for pharmacological intervention of tumor vascularization.