title: Secretion of VEGF-165 has unique characteristics, including shedding from the plasma membrane.
abstract: Vascular endothelial growth factor (VEGF) is a critical regulator of endothelial cell differentiation and vasculogenesis during both development and tumor vascularization. VEGF-165 is a major form that is secreted from the cells via a poorly characterized pathway. Here we use green fluorescent protein- and epitope-tagged VEGF-165 and find that its early trafficking between the endoplasmic reticulum and the Golgi requires the small GTP-binding proteins Sar1 and Arf1 and that its glycosylation in the Golgi compartment is necessary for efficient post-Golgi transport and secretion from the cells. The relative temperature insensitivity of VEGF secretion and its Sar1 and Arf1 inhibitory profiles distinguish it from other cargoes using the "constitutive" secretory pathway. Prominent features of VEGF secretion are the retention of the protein on the outer surface of the plasma membrane and the stimulation of its secretion by Ca(2+) and protein kinase C. Of importance, shedding of VEGF-165 from the cell surface together with other membrane components appears to be a unique feature by which some VEGF is delivered to the surroundings to exert its known biological actions. Understanding VEGF trafficking can reveal additional means by which tumor vascularization can be inhibited by pharmacological interventions.
authors: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 Department of Neurosciences, University of Geneva, 1211 Geneva 4, Switzerland.
authors: Maria Luisa
authors: ML
authors: Guzmán-Hernández
authors: Gael
authors: G
authors: Potter
authors: Kristóf
authors: K
authors: Egervári
authors: Jozsef Z
authors: JZ
authors: Kiss
authors: Tamas
authors: T
authors: Balla
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; D020123:Sirolimus