Nucleocytoplasmic Localization of MAPKs

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Nucleocytoplasmic Localization of MAPKs

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Title: Nucleocytoplasmic Localization of MAPKs
Author: Yazicioglu, Mustafa Naci
Abstract: Mitogen-activated protein kinases (MAPKs) comprise a family of protein-serine/threonine kinases, which participate in signal transduction pathways that control intracellular events. MAPKs are regulated by phosphorylation cascades, which are usually initiated by external stimuli including a variety of ligands. At least two upstream protein kinases are activated in series to lead to activation of a MAPK. The kinase that activates the MAPK is a MAPK kinase (MAP2K or MEK) and the kinase that phosphorylates the MAP2K is a MAP3K or MEK kinase (MEKK). Upon activation, MAPKs may translocate to the nucleus to phosphorylate nuclear targets. Previous findings from our laboratory showed that a constitutively active and nuclear form of the MAPK ERK2 is sufficient for transformation of immortalized fibroblasts (Robinson MJ et al,1998). However the mechanisms of nuclear localization of MAPKs are still not fully understood clearly. Although most nucleocytoplasmic localization events require carrier proteins known as karyopherins (importins and exportins), ERK2 enters the nucleus of permeabilized cells even if these carrier proteins are missing. This is explained by direct binding to proteins in the nuclear pore complex (NPC). Similar to ERK2 targets, NPC proteins also contain Phe-Xxx-Phe (FXF) motifs. My first aim in this project was to examine the roles of ERK2 residues that are crucial for FXF binding on nuclear localization of ERK2. Mutating these ERK2 residues decreased the nuclear import of ERK2 proteins in permeabilized cells. Secondly, the regulation of ERK2 nuclear export was analyzed. It was observed that ERK2 export occurs by two distinct processes; one energy-dependent and the other energy-independent. My final aim was analyzing the activation and nucleocytoplasmic trafficking of other MAPKs, JNK and p38.
URI: http://hdl.handle.net/2152.5/647
Date: 2007-08-08

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