Dokument

Summary:
Hedgehog signaling (Hh) plays a crucial role in vital processes such as embryonic development or cell homeostasis. Aberrant Hh signaling is linked to formation, progression, and growth of tumors. The canonical Hh signaling cascade is initiated by binding of the Hh ligand to its receptor Patched1 (PTCH1) (Hooper and Scott 1989; Nakano et al. 1989), a transmembrane protein located in the ciliary membrane which relieves the repression of the membrane-bound G protein-coupled receptor (GPCR) Smoothened (SMO) which activates the Hh transcriptional factors, zinc finger proteins of the GLI (Cubitus interruptus (Ci) in Drosophila melanogaster) family (Hui and Angers 2011). The Hh signaling pathway is reported to activate downstream kinases which in turn lead to various cellular processes such as differentiation, polarity, and proliferation. The so-called dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) are induced by Hh activation and a slight change in their amount could lead to large and significant effects on various cellular processes. DYRK1A as a candidate gene is responsible for the altered neuronal development and brain abnormalities in Down syndrome (DS, OMIM #190685). DYRK1B is known to be associated with the metabolic syndrome and, is commonly amplified in ovarian and pancreatic cancer (Friedman 2010a; Keramati et al. 2014b). The results of the present work have shown, that Hh signaling induces DYRK1B and this kinase has been shown to have a regulatory kinetic effect on Hh signaling pathway, as short-term inhibition of DYRK1B kinase leads to increase in GLI protein levels and long-term inhibition has shown to deplete the protein levels of GLI. This strong fluctuation in the kinase could be detrimental in a therapeutical context, as DYRK1B has been shown to regulate PI3K/mTOR/AKT signaling pathway which is subject to strong feedback regulation and can induce oncogenic Hh signaling. Combination therapy which targets DYRK1B and other signaling pathway components such as mTOR, AKT, S6K were used to deplete growth of pancreatic and ovarian cancer cells. Hh signaling exerts myriad functions and one of the functions is to induce acetylation of microtubules and of Acetylated Tubulin (AcTub)-dependent processes such as cell polarization or organelle transport. With my results, I find that Hh signaling increases DYRK1B levels, which inactivates Glycogen synthase kinase 3β (GSK3β) through Serine 9 (Ser9) phosphorylation, resulting in Histone Deacetylase 6 (HDAC6) inhibition and increased tubulin acetylation. In summary, I have described a mechanistic framework of how intercellular communication can impinge on cytoskeletal regulation and cell function via Hh signal transduction. Considering these effects, I have shown that DYRK1B is one of the very crucial kinases mediating multiple signaling pathways and; thereby, it’s extremely important to elucidate the mechanistic framework of its action.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten