title: Plakophilin 2 affects cell migration by modulating focal adhesion dynamics and integrin protein expression.
abstract: Plakophilin 2 (PKP2), a desmosome component, modulates the activity and localization of the small GTPase RhoA at sites of cell-cell contact. PKP2 regulates cortical actin rearrangement during junction formation, and its loss is accompanied by an increase in actin stress fibers. We hypothesized that PKP2 may regulate focal adhesion dynamics and cell migration. Here we show that PKP2-deficient cells bind efficiently to the extracellular matrix, but upon spreading display total cell areas ≈ 30% smaller than control cells. Focal adhesions in PKP2-deficient cells are ≈ 2 × larger and more stable than in control cells, and vinculin displays an increased time for fluorescence recovery after photobleaching. Furthermore, β4 and β1 integrin protein and mRNA expression is elevated in PKP2-silenced cells. Normal focal adhesion phenotypes can be restored in PKP2-null cells by dampening the RhoA pathway or silencing β1 integrin. However, integrin expression levels are not restored by RhoA signaling inhibition. These data uncover a potential role for PKP2 upstream of β1 integrin and RhoA in integrating cell-cell and cell-substrate contact signaling in basal keratinocytes necessary for the morphogenesis, homeostasis, and reepithelialization of the stratified epidermis.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Koetsier
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Evangeline V
authors.initials: EV
authors.lastname: Amargo
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Todorović
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: l-godsel@northwestern.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Godsel
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003896:Desmosomes / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D022001:Focal Adhesions / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D039663:Integrin beta4 / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D051191:Plakophilins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014945:Wound Healing / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D039663:Integrin beta4; C495337:PKP2 protein, human; D051191:Plakophilins; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein