FGF21 promotes endothelial cell angiogenesis through a dynamin-2 and Rab5 dependent pathway. PLoS One 2014;9(5):e98130
Date
05/23/2014Pubmed ID
24848261Pubmed Central ID
PMC4029959DOI
10.1371/journal.pone.0098130Scopus ID
2-s2.0-84901326911 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
Binding of angiogenic molecules with cognate receptor tyrosine kinases (RTK) is required for angiogenesis however the precise link between RTK binding, endocytosis, and signaling requires further investigation. Here, we use FGFR1 as a model to test the effects of the large GTPase and endocytosis regulatory molecule dynamin-2 on angiogenic signaling in context of distinct FGF ligands. In vitro, overexpression of dominant negative dynamin-2 (DynK44A) attenuates FGFR1 activation of Erk and tubulogenesis by FGF2. Furthermore, we identify FGF21, a non-classical, FGF ligand implicated in diverse human pathologies as an angiogenic molecule acting through FGFR1 and β-Klotho coreceptor. Disruption of FGFR1 activation of ERK by FGF21 is achieved by perturbation of the function of both dynamin-2 and Rab5 GTPase. In vivo, mice harboring endothelial selective overexpression of DynK44A, show impaired angiogenesis in response to FGF21. In conclusion, dynamin dependent endocytosis of FGFR1 is required for in vitro and in vivo angiogenesis in response to FGF2 and the non-classical FGF ligand, FGF21. These studies extend our understanding of the relationships between RTK binding, internalization, endosomal targeting, and angiogenic signaling.
Author List
Yaqoob U, Jagavelu K, Shergill U, de Assuncao T, Cao S, Shah VHAuthor
Thiago Milech De Assuncao Research Scientist II in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDynamin II
Endocytosis
Endosomes
Endothelial Cells
Fibroblast Growth Factor 2
Fibroblast Growth Factors
Gene Expression Regulation
Human Umbilical Vein Endothelial Cells
Humans
Ligands
Liver Cirrhosis
Male
Membrane Proteins
Mice
Mice, Transgenic
Neovascularization, Pathologic
Protein Binding
Signal Transduction
rab5 GTP-Binding Proteins
