title: BAG-1 enhances cell-cell adhesion, reduces proliferation and induces chaperone-independent suppression of hepatocyte growth factor-induced epidermal keratinocyte migration.
abstract: Cell motility is important in maintaining tissue homeostasis, facilitating epithelial wound repair and in tumour formation and progression. The aim of this study was to determine whether BAG-1 isoforms regulate epidermal cell migration in in vitro models of wound healing. In the human epidermal cell line HaCaT, endogenous BAG-1 is primarily nuclear and increases with confluence. Both transient and stable p36-Bag-1 overexpression resulted in increased cellular cohesion. Stable transfection of either of the three human BAG-1 isoforms p36-Bag-1 (BAG-1S), p46-Bag-1 (BAG-1M) and p50-Bag-1 (BAG-1L) inhibited growth and wound closure in serum-containing medium. However, in response to hepatocyte growth factor (HGF) in serum-free medium, BAG-1S/M reduced communal motility and colony scattering, but BAG-1L did not. In the presence of HGF, p36-Bag-1 transfectants retained proliferative response to HGF with no change in ERK1/2 activation. However, the cells retained E-cadherin localisation at cell-cell junctions and exhibited pronounced cortical actin. Point mutations in the BAG domain showed that BAG-1 inhibition of motility is independent of its function as a chaperone regulator. These findings are the first to suggest that BAG-1 plays a role in regulating cell-cell adhesion and suggest an important function in epidermal cohesion.
authors.affiliation: Oral and Dental Science, University of Bristol, Lower Maudlin Street, Bristol, BS1 2LY, UK.
authors.forename: C A M
authors.initials: CA
authors.lastname: Hinitt
authors.forename: J
authors.initials: J
authors.lastname: Wood
authors.forename: S S
authors.initials: SS
authors.lastname: Lee
authors.forename: A C
authors.initials: AC
authors.lastname: Williams
authors.forename: J L
authors.initials: JL
authors.lastname: Howarth
authors.forename: C P
authors.initials: CP
authors.lastname: Glover
authors.forename: J B
authors.initials: JB
authors.lastname: Uney
authors.forename: A
authors.initials: A
authors.lastname: Hague
mesh_terms: D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018833:Chaperonins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D000078404:Epidermal Cells; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects; D014157:Transcription Factors / Q000502:physiology*; D014945:Wound Healing
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D018833:Chaperonins