Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome.
Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.
Lai-Cheong
J E
JE
Genetic Skin Disease Group, St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.
Ussar
S
S
Arita
K
K
Hart
I R
IR
McGrath
J A
JA
D001706:Biopsy; D001768:Blister / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010787:Photosensitivity Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012873:Skin Diseases, Genetic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013577:Syndrome
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C473794:FBLIM1 protein, human; C475301:FERMT1 protein, human; C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger