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Regulation of epithelial plasticity by ERK1 and ERK2 isoforms
Rasl, Jan ; Vomastek, Tomáš (advisor) ; Rösel, Daniel (referee) ; Libusová, Lenka (referee)
The ERK pathway is an evolutionarily conserved three-tier signaling cascade comprised of protein kinases Raf, MEK, and ERK. These core kinases are arranged in a hierarchical order and the signal is transduced from Raf to MEK to ERK. The ERK pathway is activated by diverse extracellular signals and in response regulates many cellular processes including cell proliferation, differentiation, apoptosis, migration or epithelial plasticity. Given the role of the ERK pathway in regulating such fundamental cellular processes, the ERK pathway signaling is tightly controlled and its dysregulation has pathological consequences such as cancer development and progression. Although much is known about mechanisms underlying the signal transduction by the ERK signaling pathway, much less is known about how two highly homologous ERK1 and ERK2 isoforms contribute to the signaling by this pathway. In this thesis, I studied isoform-specific functions of ERK1 and ERK2 using epithelial Madin- Darby Canine Kidney (MDCK) cells overexpressing either ERK1 or ERK2. Obtained data show that overexpression of ERK2, but not ERK1, had significant effects on the morphology and functional phenotype of MDCK cells. Both ERK1 and ERK2 expressing cells were able to form cohesive clusters, but the only ERK2 overexpression affected...
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The regulation of cofilin by the ERK signaling cascade
Rasl, Jan ; Vomastek, Tomáš (advisor) ; Gahura, Ondřej (referee)
Cofilin is small ubiquitous actin binding protein, which is required for polymerization and depolymerization of actin fibers. Cofilin is involved in numerous cellular processes where the remodeling of actin cytoskeleton is required, such as cell division and cell migration. In order to precisely and dynamically regulate the cofilin activity, cells utilize large network of interconnected signaling pathways. One of these signaling pathways is the MAP-kinase cascade ERK (extracellular signal-regulated kinase), although the molecular mechanisms by which ERK regulates cofilin activity are not fully understood. Much evidence suggests that ERK controls the cofilin activity mainly through the regulation of Rho family of small GTPases. The ERK signaling cascade can modulates the Rho GTPase pathway signaling components, such as GAPs (GTPase activating proteins), GEFs (guanine nucleotide exchange factors) or Rho GTPases effectors. The ERK signaling cascade utilizes two different mechanisms for the regulation of Rho GTPases signaling pathways. The first mechanism is on transcriptional and translational level, where ERK regulates the transcription and subsequently translation of key regulatory proteins. Second mechanism, which is far more dynamic, occurs at the level of posttranslational modification,...
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Regulation of actin cytoskeleton and epithelial cells morphology by the ERK signaling pathway
Rasl, Jan ; Vomastek, Tomáš (advisor) ; Tolde, Ondřej (referee)
The ERK signalling cascade belongs to a familly of the signalling pathways conserved in eukaryotic cells, which responds to the wide spectrum of extracellular stimuli and convert these stimuli to appropriate response. In epithelial cells the ERK signalling cascade induces disintegration of epithelial architecture and induces morphological changes leading to the gain of the autonomy of the epithelial cells. During morphological changes of the epithelial structure, the ERK signalling cascade participates in the remodelling of the actin cytoskeleton, which leads to the disassembly of cell-cell adhesions and the loss of the epithelial polarity. Subsequently ERK activates the migration programme, which enables epithelial cells to use individual mesenchymal-like mode of migration. The so called peripheral actin is one of the least explored actin structures that forms at the periphery of the epithelial cells and surrounds the colony of epithelial cells. Peripheral actin is located at the basal side of the cell and it probably takes part in the integrity of epithelial tissue. Nevertheless, up to date it is not know if and how ERK signalling cascade regulatesthe peripheral actin and if remodeling of peripheral actin takes part in the cell migration. In this thesis we show, that ERK signalling cascade is...
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Regulation of actin cytoskeleton and epithelial cells morphology by the ERK signaling pathway
Rasl, Jan ; Vomastek, Tomáš (advisor) ; Tolde, Ondřej (referee)
The ERK signalling cascade belongs to a familly of the signalling pathways conserved in eukaryotic cells, which responds to the wide spectrum of extracellular stimuli and convert these stimuli to appropriate response. In epithelial cells the ERK signalling cascade induces disintegration of epithelial architecture and induces morphological changes leading to the gain of the autonomy of the epithelial cells. During morphological changes of the epithelial structure, the ERK signalling cascade participates in the remodelling of the actin cytoskeleton, which leads to the disassembly of cell-cell adhesions and the loss of the epithelial polarity. Subsequently ERK activates the migration programme, which enables epithelial cells to use individual mesenchymal-like mode of migration. The so called peripheral actin is one of the least explored actin structures that forms at the periphery of the epithelial cells and surrounds the colony of epithelial cells. Peripheral actin is located at the basal side of the cell and it probably takes part in the integrity of epithelial tissue. Nevertheless, up to date it is not know if and how ERK signalling cascade regulatesthe peripheral actin and if remodeling of peripheral actin takes part in the cell migration. In this thesis we show, that ERK signalling cascade is...
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The regulation of cofilin by the ERK signaling cascade
Rasl, Jan ; Vomastek, Tomáš (advisor) ; Gahura, Ondřej (referee)
Cofilin is small ubiquitous actin binding protein, which is required for polymerization and depolymerization of actin fibers. Cofilin is involved in numerous cellular processes where the remodeling of actin cytoskeleton is required, such as cell division and cell migration. In order to precisely and dynamically regulate the cofilin activity, cells utilize large network of interconnected signaling pathways. One of these signaling pathways is the MAP-kinase cascade ERK (extracellular signal-regulated kinase), although the molecular mechanisms by which ERK regulates cofilin activity are not fully understood. Much evidence suggests that ERK controls the cofilin activity mainly through the regulation of Rho family of small GTPases. The ERK signaling cascade can modulates the Rho GTPase pathway signaling components, such as GAPs (GTPase activating proteins), GEFs (guanine nucleotide exchange factors) or Rho GTPases effectors. The ERK signaling cascade utilizes two different mechanisms for the regulation of Rho GTPases signaling pathways. The first mechanism is on transcriptional and translational level, where ERK regulates the transcription and subsequently translation of key regulatory proteins. Second mechanism, which is far more dynamic, occurs at the level of posttranslational modification,...
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