title: Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells.
abstract: 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.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, CNRS UMR 8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Paris, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Allain
authors.forename: Rafika
authors.initials: R
authors.lastname: Jarray
authors.forename: Lucia
authors.initials: L
authors.lastname: Borriello
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leforban
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dufour
authors.forename: Wang-qing
authors.initials: WQ
authors.lastname: Liu
authors.forename: Perayot
authors.initials: P
authors.lastname: Pamonsinlapatham
authors.forename: Sara
authors.initials: S
authors.lastname: Bianco
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Réda
authors.initials: R
authors.lastname: Hadj-Slimane
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
authors.forename: Yves
authors.initials: Y
authors.lastname: Lepelletier
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D018929:Cell Culture Techniques; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism*; D034622:RNA Interference; D059008:Time-Lapse Imaging; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; C570134:PHACTR1 protein, human; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040281:Vascular Endothelial Growth Factor Receptor-1