| الملخص: |
The structure of human epidermis is maintained by a balance between proliferation and differentiation of keratinocytes. The source of all epidermal keratinocytes is a population of epidermal stem cells in the basal layer of the epidermis that keeps proliferating through adult life and gives rise to committed daughters, transit amplifying cells. After a few rounds of divisions these daughter cells undergo a maturation process called terminal differentiation. Integrin receptors transduce signals from extracellular matrix molecules into the cell and thereby control both exit from the stem cell compartment and the onset of terminal differentiation. The aim of my PhD project was to investigate signalling pathways by which integrins exert these effects. I found that integrins of the β1 subfamily can regulate the activity of mitogen activated protein kinase (MAPK) in keratinocytes. Detachment of keratinocytes from culture dishes prevented activation of MAPK. Partial inhibition of integrin function by introduction of a dominant inhibitory β1 integrin mutant caused reduced MAPK activity and decreased proliferative potential. This reduction in proliferative potential was due to inhibition of MAPK signalling since it could be restored by adhesion independent activation of MAPK. Inhibition of MAPK caused decreased proliferative potential and adhesiveness in the absence of the dominant negative integrin. Modulation of MAPK activity in adherent and suspended keratinocytes and in organotypic cultures revealed that MAPK activity regulated proliferation, migration and terminal differentiation. In reconstituted epidermis in vitro MAPK activation caused histological changes typical of hyperproliferative skin diseases. Using nuclear localization of MAPK as a readout for its activity I found increased MAPK activity in psoriatic lesions of human skin and in healing skin wounds of mice. My results indicate a function of integrin dependent MAPK signalling in the regulation of keratinocyte differentiation and in the development of hyperproliferative skin conditions. |
