title: Kindlin-1 regulates integrin dynamics and adhesion turnover.
abstract: Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Coert
authors.initials: C
authors.lastname: Margadant
authors.forename: Maaike
authors.initials: M
authors.lastname: Kreft
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
mesh_terms: D001768:Blister / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism; D004820:Epidermolysis Bullosa / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010510:Periodontal Diseases / Q000235:genetics / Q000378:metabolism; D010787:Photosensitivity Disorders / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding
chemical_list: C475301:FERMT1 protein, human; C477322:FERMT3 protein, human; D019012:Integrin beta1; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins