title: PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis.
abstract: Basolateral polymerization of cellular fibronectin (FN) into a meshwork drives endothelial cell (EC) polarity and vascular remodelling. However, mechanisms coordinating α5β1 integrin-mediated extracellular FN endocytosis and exocytosis of newly synthesized FN remain elusive. Here we show that, on Rab21-elicited internalization, FN-bound/active α5β1 is recycled to the EC surface. We identify a pathway, comprising the regulators of post-Golgi carrier formation PI4KB and AP-1A, the small GTPase Rab11B, the surface tyrosine phosphatase receptor PTPRF and its adaptor PPFIA1, which we propose acts as a funnel combining FN secretion and recycling of active α5β1 integrin from the trans-Golgi network (TGN) to the EC surface, thus allowing FN fibrillogenesis. In this framework, PPFIA1 interacts with active α5β1 integrin and localizes close to EC adhesions where post-Golgi carriers are targeted. We show that PPFIA1 is required for FN polymerization-dependent vascular morphogenesis, both in vitro and in the developing zebrafish embryo.
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo, Torino 10060, Italy.|Laboratory of Cell Adhesion Dynamics, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Mana
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo, Torino 10060, Italy.|Laboratory of Cell Adhesion Dynamics, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Clapero
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Panieri
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Panero
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Böttcher
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Hui-Yuan
authors.initials: HY
authors.lastname: Tseng
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo, Torino 10060, Italy.|Laboratory of Cell Adhesion Dynamics, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Saltarin
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo, Torino 10060, Italy.|Laboratory of Vascular Oncology, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Astanina
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Katarzyna I
authors.initials: KI
authors.lastname: Wolanska
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morgan
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine &Health, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.|Laboratory of Endothelial Molecular Biology, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
authors.forename: Massimo M
authors.initials: MM
authors.lastname: Santoro
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo, Torino 10060, Italy.|Laboratory of Cell Adhesion Dynamics, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy.
authors.forename: Guido
authors.identifier: 0000-0002-3502-8367
authors.initials: G
authors.lastname: Serini
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo, Torino 10060, Italy.|Laboratory of Cell Adhesion Dynamics, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Torino 10060, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Valdembri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006056:Golgi Apparatus / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology; D015027:Zebrafish
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005353:Fibronectins; D039081:Integrin alpha5beta1; C094398:PPFIA1 protein, human