Nuclear speckles and nucleoli targeting by PIP2–PDZ domain interactions

• Published in: The EMBO journal Vol. 24; no. 14; pp. 2556 - 2565
• Main Authors: Mortier, Eva, Wuytens, Gunther, Leenaerts, Iris, Hannes, Femke, Heung, Man Y, Degeest, Gisèle, David, Guido, Zimmermann, Pascale
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 20.07.2005; Blackwell Publishing Ltd
• Subjects: Carrier Proteins - metabolism; Cell Division - physiology; Cell Line, Tumor; Cell Membrane - metabolism; Cell Nucleolus - metabolism; Cell Nucleus - metabolism; Cell Survival - physiology; Cells, Cultured; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Lipid Bilayers - metabolism; Membrane Proteins - metabolism; Nerve Tissue Proteins - metabolism; nuclear speckles; nucleoli; PDZ domain; Phosphatidylinositol 4,5-Diphosphate - metabolism; phosphoinositides; Protein Interaction Mapping; Protein Structure, Tertiary; Proteins; syntenin; Syntenins; Time Factors
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600722

PDZ (Postsynaptic density protein, Disc large, Zona occludens) domains are protein–protein interaction modules that predominate in submembranous scaffolding proteins. Recently, we showed that the PDZ domains of syntenin‐1 also interact with phosphatidylinositol 4,5‐bisphosphate (PIP2) and that this interaction controls the recruitment of the protein to the plasma membrane. Here we evaluate the general importance of PIP2–PDZ domain interactions. We report that most PDZ proteins bind weakly to PIP2, but that syntenin‐2, the closest homolog of syntenin‐1, binds with high affinity to PIP2 via its PDZ domains. Surprisingly, these domains target syntenin‐2 to nuclear PIP2 pools, in nuclear speckles and nucleoli. Targeting to these sites is abolished by treatments known to affect these PIP2 pools. Mutational and domain‐swapping experiments indicate that high‐affinity binding to PIP2 requires both PDZ domains of syntenin‐2, but that its first PDZ domain contains the nuclear PIP2 targeting determinants. Depletion of syntenin‐2 disrupts the nuclear speckles–PIP2 pattern and affects cell survival and cell division. These findings show that PIP2–PDZ domain interactions can directly contribute to subnuclear assembly processes.