title: Kindlin-1 Regulates Keratinocyte Electrotaxis.
abstract: Kindler syndrome (KS) is an autosomal recessive blistering skin disease resulting from pathogenic mutations in FERMT1. This gene encodes kindlin-1, a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective cell adhesion and migration. Electric fields also act as intrinsic regulators of adhesion and migration in the skin, but the molecular mechanisms by which this occurs are poorly understood. Here we show that keratinocytes derived from KS patients are unable to undergo electrotaxis, and this defect is restored by overexpression of wild-type kindlin-1 but not a W612A mutation that prevents kindlin-integrin binding. Moreover, deletion of the pleckstrin homology domain of kindlin-1 also failed to rescue electrotaxis in KS cells, indicating that both integrin and lipid binding are required for this function. Kindlin-1 was also required for the maintenance of lamellipodial protrusions during electrotaxis via electric field-activated β1 integrin. Indeed, inhibition of β1 integrins also leads to loss of electrotaxis in keratinocytes. Our data suggest that loss of kindlin-1 function may therefore result in epithelial insensitivity to electric fields and contribute to KS disease pathology.
authors.affiliation: Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China; School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Kings College London, London, UK.
authors.forename: Rumena
authors.initials: R
authors.lastname: Begum
authors.affiliation: Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China.
authors.forename: Hongduo
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Gao
authors.affiliation: St. Johns Institute of Dermatology, King's College London, Guys Campus, London, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Kings College London, London, UK. Electronic address: maddy.parsons@kcl.ac.uk.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China; School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK. Electronic address: SongB3@cardiff.ac.uk.
authors.forename: Bing
authors.initials: B
authors.lastname: Song
mesh_terms: D001768:Blister / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010510:Periodontal Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010787:Photosensitivity Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000166:cytology / Q000378:metabolism*
chemical_list: C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D004247:DNA