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Project

Studie van de nucleaire functie van PDZ domein-fosfatidylinositol 4,5-bisfosfaat interacties in cellulaire en ontwikkelingsprogramma's.

PDZ proteins appear crucial in the maintenance of neuronal and epithelial polarity. And until recently, most studies tended to explain this function by an organizational role at the cell cortex, and by the property of PDZ domains to function as protein-interaction modules, recognizing short peptide sequences situated at the C-terminal end of transmembrane receptors. Our recent studies have revealed that PDZ domains can also interact with phosphoinositides (PIPs), signaling lipids with key-roles in receptor signal transduction, membrane trafficking, cytoskeleton remodeling, subcellular compartmentalization and nuclear processes. In particular, we have established that the PDZ domains of syntenin-2 bind to phosphatidylinositol 4, 5-bisphosphate (PIP2) with high-affinity. Unexpectedly, we found that syntenin-2 shuttles between plasma membrane PIP2 and nuclear PIP2 in nucleoli and nuclear speckles. Nucleoli coordinate ribosomal synthesis and assembly, but have also important non-ribosomal functions, in particular as sequestering organelles for cell cycle and survival regulators. Nuclear speckles are dynamic punctate subnuclear structures that are enriched in pre-messenger RNA splicing factors and are located in the interchromatin regions of the nucleoplasm. Our RNAi experiments indicated that syntenin-2 plays a role in the organization of nuclear PIP2 and in cell division and survival. Moreover, by screening the Drosophila PDZ proteome (containing no syntenin) for phosphoinositide interactions, we found other proteins that interact with PIP2, via their PDZ domains, and that also shuttle to subnuclear regions enriched in PIP2 (unpublished data). Lipid signaling in the nucleus is an emerging field of research. Nuclear PIP2 is implicated in chromatin remodeling and gene transcription, regulates RNA processin and controls cell growth and proliferation. Thus, we identified PDZ domains as the first modules recognizing nuclear PIP2 and by elucidating their function therein, we aim to unravel a novel aspect of the biology of PDZ proteins and to contribute to a better understanding of nuclear phosphoinositide-signaling. Specifically we aim to identify the mechanisms that regulate the nuclear targeting of PDZ proteins, testing for (i) the effect of various stimuli, (ii) the role of nuclear export and import signals, (iii) the role of phosphorylation and (iv) the importance of proteolytic cleavage. We want to elucidate whether PDZ proteins interacting with nuclear PIP2 play a role in (i) cell-cycle progression, (ii) cell-survival, (iii) mRNA processing or (iv) other nuclear processes.
Datum:1 jan 2008 →  31 dec 2013
Trefwoorden:Nuclear function of PDZ