FGD5 sustains vascular endothelial growth factor A (VEGFA) signaling through inhibition of proteasome-mediated VEGF receptor 2 degradation

• Published in: Cellular signalling Vol. 40; pp. 125 - 132
• Main Authors: Heldin, Johan, O'Callaghan, Paul, Hernández Vera, Rodrigo, Fuchs, Peder Fredlund, Gerwins, Pär, Kreuger, Johan
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.12.2017
• Subjects: Acetylcysteine - administration & dosage; Acetylcysteine - analogs & derivatives; Angiogenesis; Cdc42; Cell Membrane - genetics; Cell Membrane - metabolism; Cell Movement - drug effects; Cell Movement - genetics; Degradation; Endosomes - genetics; Endosomes - metabolism; Endothelial Cells - metabolism; FGD5; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Humans; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - genetics; Proteolysis - drug effects; Signal Transduction - drug effects; Signal Transduction - genetics; Vascular biology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2; VEGFR2; Degradation; Angiogenesis; FGD5; HMVEC; GEF; MAPK; β-PIX; siFGD5; Vascular biology; Cdc42; VEGFA
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2017.09.009

The complete repertoire of endothelial functions elicited by FGD5, a guanine nucleotide exchange factor activating the Rho GTPase Cdc42, has yet to be elucidated. Here we explore FGD5's importance during vascular endothelial growth factor A (VEGFA) signaling via VEGF receptor 2 (VEGFR2) in human endothelial cells. In microvascular endothelial cells, FGD5 is located at the inner surface of the cell membrane as well as at the outer surface of EEA1-positive endosomes carrying VEGFR2. The latter finding prompted us to explore if FGD5 regulates VEGFR2 dynamics. We found that depletion of FGD5 in microvascular cells inhibited their migration towards a stable VEGFA gradient. Furthermore, depletion of FGD5 resulted in accelerated VEGFR2 degradation, which was reverted by lactacystin-mediated proteasomal inhibition. Our results thus suggest a mechanism whereby FGD5 sustains VEGFA signaling and endothelial cell chemotaxis via inhibition of proteasome-dependent VEGFR2 degradation. •FGD5 co-localizes with VEGFR2 in early endosomes.•FGD5 silencing inhibits VEGFA-induced chemotaxis.•VEGFR2 signaling is impaired in response to FGD5 silencing.•FGD5 silencing promotes VEGFR2 proteasomal degradation.