The keratin-desmosome scaffold as a signaling module during epithelial differentiation and wound healing

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TThe keratin-desmosome scaffold has a dual role in regulating epidermal differentiation through crosstalk with growth factors, in addition to mediating intercellular adhesion and force resistance. Differentiation, wound healing and pathogenesis require remodelling of the keratin desmosome complex at various levels to mediate strong adhesion in the former and weaker adhesion in the latter setting. The functional significance of keratin isotypes for the regulation of desmosomal adhesion, epidermal differentiation and wound healing is not well understood.We have recently established a series of mice and keratinocyte cell lines that lack all or re-express distinct sets of keratins. Their analysis has revealed an active role of keratins in desmosome maintenance impacting on keratinocyte migration and invasion. We demonstrated that keratin-dependent sequestration of a Rack1 PKCa scaffold mediates desmoplakin phosphorylation, cell adhesion and regulates desmosomal protein internalization. Further, we identified a keratin isotype dependent activation of Src as an upstream regulator of desmosomal adhesion. This strongly suggests a role of keratins in inside-out signaling. We hypothesize that the keratin-desmosome scaffold acts as signalling node which receives and modulates growth factor signals in a keratin isotype dependent manner to control cell adhesion, cell signalling and to maintain epithelial cell fate.Our project will elucidate major mechanisms by which keratin isotypes affect epidermal differentiation and wound healing through regulating desmosomal adhesion and turnover. To understand this, we will dissect the crosstalk between IGFR and EGFR signalling and the keratin desmosome scaffold. The long-term aim is to understand the role of the keratin-desmosome complex during carcinogenesis and metastasis and its regulation by oncogenes and EMT activators like snail and ZEB1. To understand the interaction and regulation of the keratin-desmosome complex during keratinocyte differentiation and wound healing, we will pursue the following major objectives:1. Analysis of epidermal differentiation and wound healing as a function of keratin isotypes and their interaction with desmosomes in keratinocytes 2. Wound healing analysis in keratin deficient mice in vivo3. Response of keratin isotype desmosome interactions to signalling downstream of the IGF and EGF receptor4. Dissection of keratin isotype-dependent inside out regulation of Src kinaseWe expect that this project will contribute significantly to the role of keratin isotypes in cell adhesion and its regulation by IGF and EGF. In the long run, our data will provide a mechanistic understanding for the respective contribution of keratin isotypes to epithelial cell behaviour during wound healing and malignant transformation/metastasis. They will provide the opportunity to affect epithelial cell adhesion, migration and invasion by targeting select keratin isotypes in such settings.