Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1-dependent and p38, JNK and PI3K/Akt-independent manner

Autor: Dan Tse, B. JoNell Hamilton, Radu V. Stan
Rok vydání: 2018
Předmět:
0301 basic medicine
Vascular Endothelial Growth Factor A
VVO
Axitinib
MAP Kinase Kinase 4
Pyridines
MAP Kinase Kinase 1
Piperazines
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Caveolae
fenestrae
RNA
Small Interfering
Anthracenes
Sulfonamides
biology
Chemistry
Kinase
Imidazoles
endothelial diaphragm
Cell biology
Autocrine Communication
030220 oncology & carcinogenesis
Mitogen-activated protein kinase
Molecular Medicine
Tetradecanoylphorbol Acetate
Original Article
Signal Transduction
Indazoles
p38 mitogen-activated protein kinases
03 medical and health sciences
Downregulation and upregulation
Nitriles
Butadienes
Human Umbilical Vein Endothelial Cells
Humans
cancer
Autocrine signalling
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Flavonoids
diapedesis
Membrane Proteins
Cell Biology
Original Articles
transendothelial channel
Vascular Endothelial Growth Factor Receptor-2
030104 developmental biology
Pyrimidines
Gene Expression Regulation
inflammation
caveolae
biology.protein
permeability
Proto-Oncogene Proteins c-akt
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
Popis: Endothelial diaphragms are subcellular structures critical for mammalian survival with poorly understood biogenesis. Plasmalemma vesicle associated protein (PLVAP) is the only known diaphragm component and is necessary for diaphragm formation. Very little is known about PLVAP regulation. Phorbol esters (PMA) are known to induce de novo PLVAP expression and diaphragm formation. We show that this induction relies on the de novo production of soluble factors that will act in an autocrine manner to induce PLVAP transcription and protein expression. We identified vascular endothelial growth factor‐A (VEGF‐A) signalling through VEGFR2 as a necessary but not sufficient downstream event as VEGF‐A inhibition with antibodies and siRNA or pharmacological inhibition of VEGFR2 only partially inhibit PLVAP upregulation. In terms of downstream pathways, inhibition of MEK1/Erk1/2 MAP kinase blocked PLVAP upregulation, whereas inhibition of p38 and JNK MAP kinases or PI3K and Akt had no effect on PMA‐induced PLVAP expression. In conclusion, we show that VEGF‐A along with other secreted proteins act synergistically to up‐regulate PLVAP in MEK1/Erk1/2 dependent manner, bringing us one step further into understanding the genesis of the essential structures that are endothelial diaphragms.
Databáze: OpenAIRE
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