HA 1791/10-1: Charakterisierung der desmosomalen Plakophiline als Signalzentren in der Epidermis

Plakophilins (PKP) 1-3 are considered as "dual function proteins” with a structural role in desmosomes and a signaling function in the cytoplasm and/or nucleus. We have shown previously that PKP1 regulates protein synthesis via the translation initiation factor eIF4A1. The stimulation of translation by cytoplasmic PKP1 leads to an increase in cell proliferation and cell size (Wolf et al., 2010). Growth factor signaling promotes proliferation at various levels. The IGF1-PI3K-AKT-mTOR signaling axis stimulates translation which is a prerequisite for enhanced proliferation. Accordingly, we found that PKP1 function in translation is regulated by insulin/IGF-1 signaling via Akt2-mediated phosphorylation. Whereas un-phosphorylated PKP1 stabilizes cell adhesion in the desmosome, its phosphorylated form promotes proliferation in the cytoplasm and can induce anchorage-independent growth, a hallmark of cancer (Wolf et al., 2013). Our studies support a context-dependent role for PKP1 in tissue regeneration and wound healing as well as tumor formation. PKP1 and 3 reveal distinct expression patterns in the epidermis which correlates with distinct size and organization of the desmosomes in the specific epidermal layers. In this projekct we aimed to elucidate the role of PKP3 in desmosome organization and stability and how it is regulated by growth factor signaling.