Uudet filamiineista riippuvaiset mekanos

Päärahoittaja

Rahoittajan antama koodi/diaarinumero: 278668

Päärahoittajan myöntämä tuki (€)

Rahoitusohjelma

Hankkeen aikataulu

Hankkeen aloituspäivämäärä: 01.09.2014

Hankkeen päättymispäivämäärä: 31.12.2019

Tiivistelmä

It has been recently discovered that cells sense the mechanical properties of their surroundings in order to form three-dimensional tissues. This mechano-signaling includes actin cytoskeleton-linked force sensors that trigger further signaling events. My group has identified the structural mechanism how the actin crosslinking protein filamin can act as a force sensor by exposing cryptic binding sites. Using Drosophila melanogaster as a model organism we have now for the first time shown that the force sensor structure in filamin is essential for morphogenetic processes during oogenesis. In this project, we propose to combine structural biology with the Drosophila model to biochemically and genetically map the mechanically regulated signaling pathways downstream of filamin. We have already generated mechanically hypo-sensitive and hyper-sensitive mutants that provide unique and specific tools for these studies. We will utilize genomic insertions of fluorescent proteins to visualize the localization and dynamics of the mutants in live tissues. This will be linked to structural studies of filamin interactions with signaling tyrosine kinases. The proposal is basic cell biological research that aims for understanding of thus far poorly characterized but ubiquitous and evolutionary conserved cellular mechanisms. The Drosophila system provides us with a unique opportunity to study these events. The study is expected to be relevant for the understanding of tissue development in general and the diseases associated with rare human filamin mutations. The results may also partly explain the role of filamin as a marker for certain malignant cancer subtypes.

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