Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells.
Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We reported that Phactr-1 gene silencing inhibited tube formation in human umbilical endothelial cells (HUVECs) indicating a key role for Phactr-1 in tubulogenesis in vitro. In this study, we investigated the role of Phactr-1 in ... several cellular processes related to angiogenesis. We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect. We described a new interaction site of VEGF-A(165) to VEGF-R1 in peptides encoded by exons 7 and 8 of VEGF-A(165). The specific inhibition of VEGF-A(165) binding on NRP-1 and VEGF-R1 by ERTCRC and CDKPRR peptides decreased the Phactr-1 mRNA levels in HUVECs indicating that VEGF-A(165)-dependent regulation of Phactr-1 expression required both NRP-1 and VEGF-R1 receptors. In addition, upon VEGFA(165)-stimulation Phactr-1 promotes formation and maintenance of cellular tubes through NRP-1 and VEGFR1. Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.
Mesh Terms:
Amino Acid Sequence, Binding, Competitive, Cell Culture Techniques, Cell Movement, Cells, Cultured, Endothelial Cells, Gene Knockdown Techniques, Human Umbilical Vein Endothelial Cells, Humans, Microfilament Proteins, Microtubules, Neovascularization, Pathologic, Neuropilin-1, Peptide Fragments, Protein Binding, Pseudopodia, RNA Interference, Time-Lapse Imaging, Transcription, Genetic, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1
Amino Acid Sequence, Binding, Competitive, Cell Culture Techniques, Cell Movement, Cells, Cultured, Endothelial Cells, Gene Knockdown Techniques, Human Umbilical Vein Endothelial Cells, Humans, Microfilament Proteins, Microtubules, Neovascularization, Pathologic, Neuropilin-1, Peptide Fragments, Protein Binding, Pseudopodia, RNA Interference, Time-Lapse Imaging, Transcription, Genetic, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1
Cell. Signal.
Date: Jan. 01, 2012
PubMed ID: 21939755
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