Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome.

Abstract

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.

• Authors: J E Lai-Cheong, S Ussar, K Arita, I R Hart, J A McGrath
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 128 Issue 9 Pg. 2156-65 (Sep 2008) ISSN: 1523-1747 [Electronic] United States
• PMID: 18528435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Cytoskeletal Proteins
• FBLIM1 protein, human
• FERMT1 protein, human
• FERMT3 protein, human
• Membrane Proteins
• Neoplasm Proteins
• RNA, Messenger

Topics

• Biopsy
• Blister (metabolism, pathology, physiopathology)
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Line
• Cells, Cultured
• Cytoskeletal Proteins (genetics, metabolism)
• Focal Adhesions (metabolism, pathology)
• Gene Expression Regulation
• Humans
• Keratinocytes (metabolism, pathology)
• Membrane Proteins (genetics, metabolism)
• Mutation (genetics, physiology)
• Neoplasm Proteins (genetics, metabolism)
• Photosensitivity Disorders (metabolism, pathology, physiopathology)
• RNA Interference
• RNA, Messenger (metabolism)
• Skin (metabolism, pathology)
• Skin Diseases, Genetic (metabolism, pathology, physiopathology)
• Syndrome