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The regulation of the ERK signalling pathway by scaffold protein RACK1
Bráborec, Vojtěch ; Vomastek, Tomáš (advisor) ; Filipp, Dominik (referee)
The ERK signalling cascade comprised of protein kinases Raf, MEK and ERK is an evolutionarily conserved member of MAPK family that is activated in response to wide range of extracellular stimuli. The ERK pathway controls fundamental cellular functions including cell proliferation, differentiation, apoptosis or cell motility. To control such a diverse cellular responses by a single pathway cells have evolved regulatory mechanisms that channel the extracellular signals towards the specific biological response. Crucial to this control are non- enzymatic proteins termed scaffolds that associate with and enhance functional interaction of the components of MAPK pathways and can regulate amplitude, timing, specificity and location of signals. Scaffold protein RACK1 associates with several components of cell migration machinery including integrins, FAK, Src and the ERK pathway core protein kinases. RACK1 regulates distinct steps of cell migration such as establishment of cell polarity and focal adhesion turnover, however, the molecular mechanism by which RACK1 regulates these processes remains largely unknown. The main aim of this study was to investigate the functional role of RACK1 in cell motility, in particular to identify new effector proteins utilized by the ERK pathway and RACK1 in the regulation of...
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Structural basis of cell invasion
Hrčkulák, Dušan ; Novotný, Marian (advisor) ; Hájková, Zuzana (referee)
Mezenchymal migration strategy is a mode of individual cell invasion, along with an ameboid migration strategy. It is dependent on cell adhesion structures formation and traction forces generation. This work is focused on integrin-mediated cell to extracellular matrix connections called focal adhesions. Focal adhesions are very complex and comprise of many proteins. The clusters of integrin dimers make up the focal adhesion core that binds extracellular matrix. Their intracellular domains indirectly interact with actin stress fibres throught plaque proteins talin and vinculin. Focal adhesion assembly is force dependent and its commponents turnover is also regulated by focal adhesion kinase and prolin-rich tyrosin kinase 2. These kinases are probably recruited to focal adhesions by paxillin and then linked to signaling complexes by adaptor proteins as p130Cas. The 3D structure is what defines the options of interaction among participating proteins. Therefore, this work summarizes 3D structures of six proteins of interest, deals with their interactions and impact on focal adhesions. PDB codes of all available structures of these six proteins are enclosed.
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