Project Details
Projekt
Keratin-dependent regulation of desmosome composition and actin organization
Applicant
Professor Dr. Thomas Magin
Subject Area
Cell Biology
Term
from 2015 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 273121961
The mammalian epidermis is a multilayered epithelium that protects the body against physical and chemical insults by virtue of keratinocytes that are held together by desmosomes connected to cytoskeletal keratins. Epidermal differentiation, wound healing and barrier formation require constant remodeling of desmosomes and the keratin cytoskeleton to transform cuboidal keratinocytes into flat corneocytes for barrier formation and into migratory keratinocytes to promote wound repair. This remodeling requires differentiation-specific expression of isotypes of keratins and desmosomal proteins. It is regulated by growth factors and mechanical force and requires cross-talk to the actin cytoskeleton. Little is known about mechanisms by which keratin isotypes regulate desmosome composition and adhesive strength and how these changes are coordinated with the actin cytoskeleton and adherens junctions.During the first funding period, we have found that keratin isotype composition serves as a regulator of desmosome composition and adhesive strength. Whereas K14 expression led to stable desmosomes with high levels of Dsg1 and low C-terminal phosphorylation of desmoplakin, expression of K17 reduced Dsg1 at mRNA and protein levels and increased Dsg3, in addition to increasing C-terminal desmoplakin phosphorylation. Collectively, these changes weakened intercellular adhesion. Further, K17 expression coincided with decreased cortical actin organization in keratinocytes, similar to observations in the skin of keratin-deficient mice. In the skin, altered actin organization coincided with failure of keratinocytes to flatten during barrier formation. In the second funding period, we want to test the hypothesis that keratin isotypes regulate desmosome composition and adhesive strength through direct protein interactions with desmoplakin and plakophilin, and indirectly, through posttranslational protein modifications. To that end, we will focus on phosphorylation of select protein domains. Further, we want to examine whether keratins, via Dsg1, affect cortical actin organization and thereby mediate keratinocyte flattening during epidermal differentiation. We will test our hypothesis by exploiting our panel of mouse keratinocytes re-expressing keratin isotypes and variants, in addition to transgenic mice.We expect that our project provides an understanding how members of the keratin family regulate intercellular adhesion through interaction with desmosomal proteins.
DFG Programme
Priority Programmes
