title: The prion protein inhibits monocytic cell migration by stimulating β1 integrin adhesion and uropod formation.
abstract: The broad tissue distribution and evolutionary conservation of the glycosylphosphatidylinositol (GPI)-anchored prion protein (PrP, also known as PRNP) suggests that it plays a role in cellular homeostasis. Given that integrin adhesion determines cell behavior, the proposed role of PrP in cell adhesion might underlie the various in vitro and in vivo effects associated with PrP loss-of-function, including the immune phenotypes described in PrP(-/-) mice. Here, we investigated the role of PrP in the adhesion and (transendothelial) migration of human (pro)monocytes. We found that PrP regulates β1-integrin-mediated adhesion of monocytes. Additionally, PrP controls the cell morphology and migratory behavior of monocytes: PrP-silenced cells show deficient uropod formation on immobilized VCAM and display bleb-like protrusions on the endothelium. Our data further show that PrP regulates ligand-induced integrin activation. Finally, we found that PrP controls the activation of several proteins involved in cell adhesion and migration, including RhoA and its effector cofilin, as well as proteins of the ERM family. We propose that PrP modulates β1 integrin adhesion and migration of monocytes through RhoA-induced actin remodeling mediated by cofilin, and through the regulation of ERM-mediated membrane-cytoskeleton linkage.
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1066CX, The Netherlands.
authors.forename: Dion D
authors.initials: DD
authors.lastname: Richardson
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1066CX, The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: Tol
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1066CX, The Netherlands.
authors.forename: Eider
authors.initials: E
authors.lastname: Valle-Encinas
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1066CX, The Netherlands.
authors.forename: Cayetano
authors.initials: C
authors.lastname: Pleguezuelos
authors.affiliation: Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1066CX, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Bierings
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam 3015 CN, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.affiliation: Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam 1066CX, The Netherlands m.fernandez@sanquin.nl.
authors.forename: Mar
authors.initials: M
authors.lastname: Fernandez-Borja
mesh_terms: D000199:Actins; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D051338:Cofilin 1 / Q000235:genetics; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D009000:Monocytes / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D051338:Cofilin 1; D019012:Integrin beta1; D008840:Microfilament Proteins; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: Adhesion; ERM; Migration; Monocyte; Prion protein; RhoA