Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes.
Kindlin-1 is an adaptor protein that is expressed by most epithelial cells and has been implicated in integrin bidirectional signaling. Mutations in the gene encoding kindlin-1 are associated with Kindler syndrome, a recessively inherited disorder that is characterized by fragile skin. Functionally, a loss of kindlin-1 impairs the adhesion of basal keratinocytes to the extracellular matrix both in vivo and in vitro. In this study, we show that the phenotype of mutant keratinocytes deficient in kindlin-1 is characterized by the modification of the cortical actin network and increased plasticity of the plasma membrane. At the molecular level, expression of several proteins associated with an epithelial phenotype, such as α6β4 integrin, collagen XVII, E-cadherin, and desmoglein-3, is strongly reduced, whereas, surprisingly, laminin 332 is synthesized in larger amounts than in control keratinocytes. In contrast, mesenchymal markers such as vimentin and fibronectin are increased in keratinocytes lacking kindlin-1. The switch in cell plasticity and protein expression was confirmed by siRNA-mediated down-regulation of kindlin-1 in HaCaT epithelial cells. Furthermore, there was up-regulation of matrix metalloproteinases and pro-inflammatory cytokines in kindlin-1-deficient keratinocytes. These results provide new insights into the pathogenic mechanisms that take place in Kindler syndrome. Moreover, the constellation of molecular defects associated with the loss of kindlin-1 may explain the higher incidence of skin cancer observed in patients affected with this disorder.
Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
Haiyan
H
Qu
Tingting
T
Wen
Monika
M
Pesch
Monique
M
Aumailley
D008841:Actin Cytoskeleton / Q000378:metabolism; D001768:Blister / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D048430:Cell Shape / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004820:Epidermolysis Bullosa / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008858:Microscopy, Phase-Contrast; D009154:Mutation; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010510:Periodontal Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010787:Photosensitivity Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D016326:Extracellular Matrix Proteins; C475301:FERMT1 protein, human; D039663:Integrin beta4; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D020782:Matrix Metalloproteinases