FGF21 promotes endothelial cell angiogenesis through a dynamin-2 and Rab5 dependent pathway.
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.
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
Usman
U
Yaqoob
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
Kumaravelu
K
Jagavelu
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
Uday
U
Shergill
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
Thiago
T
de Assuncao
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
Sheng
S
Cao
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.
Vijay H
VH
Shah
D000818:Animals; D034285:Dynamin II / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000090265:Klotho Proteins; D008024:Ligands; D008103:Liver Cirrhosis / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
C538995:KLB protein, human; C418622:Klb protein, mouse; D008024:Ligands; D008565:Membrane Proteins; C414620:fibroblast growth factor 21; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins; C427755:RAB5C protein, human; D020696:rab5 GTP-Binding Proteins; D034285:Dynamin II