Fer kinase sustains the activation level of ERK1/2 and increases the production of VEGF in hypoxic cells.
Fer is a nuclear and cytoplasmic tyrosine kinase that is ubiquitously expressed in mammalian cells. Herein we show that Fer sustains a key signaling step in hypoxic cells. Knock-down of the Fer protein using a specific siRNA decreased the production of VEGF by the hypoxic cells. Conversely, ectopic expression of this kinase led to an elevated production of VEGF under hypoxia. At the molecular level, Fer was found to associate with ERK1/2 and this interaction was intensified under hypoxia. Moreover, Fer increased the activation levels of ERK1/2, and reducing the level of Fer, impaired the activation of ERK1/2 in hypoxic cells. Blocking the MEK-ERK1/2 signaling pathway with the MEK inhibitors U0126, or PD98059 led to the abrogation of ERK1/2 activity in hypoxic cells, an effect that was counteracted by Fer. Hence, Fer sustains the activation of ERK1/2 and increases the production of VEGF in hypoxic cells, without affecting the MEK-ERK signaling pathway.
Salem
Yaniv
Y
Faculty of Life Sciences, Bar-Ilan University, Geha Road, Ramat-Gan 52900, Israel.
Shpungin
Sally
S
Pasder
Orel
O
Pomp
Oz
O
Taler
Michal
M
Malovani
Hana
H
Nir
Uri
U
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D002070:Butadienes; D005419:Flavonoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C113580:U 0126; D042461:Vascular Endothelial Growth Factor A; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one