Nuclear speckles and nucleoli targeting by PIP2–PDZ domain interactions

Abstract

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 (PIP 2 ) and that this interaction controls the recruitment of the protein to the plasma membrane. Here we evaluate the general importance of PIP 2 -PDZ domain interactions. We report that most PDZ proteins bind weakly to PIP 2 , but that syntenin-2, the closest homolog of syntenin-1, binds with high affinity to PIP 2 via its PDZ domains. Surprisingly, these domains target syntenin-2 to nuclear PIP 2 pools, in nuclear speckles and nucleoli. Targeting to these sites is abolished by treatments known to affect these PIP 2 pools. Mutational and domain-swapping experiments indicate that high-affinity binding to PIP 2 requires both PDZ domains of syntenin-2, but that its first PDZ domain contains the nuclear PIP 2 targeting determinants. Depletion of syntenin-2 disrupts the nuclear speckles-PIP 2 pattern and affects cell survival and cell division. These findings show that PIP 2 -PDZ domain interactions can directly contribute to subnuclear assembly processes.

RETRACTED: mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB

“…A noticeable feature of mda-9/ syntenin is the presence of tandem PDZ domains of 83 and 80 amino acid residues, respectively (PDZ1 and PDZ2), which selectively bind to specific motifs at the COOH termini of partner proteins, including class B ephrins, pro-transforming growth factor-a, PTP-D, phosphatidylinositol 4,5-biphosphate, neurofaschin, neurexin, schwannomin (also known as merlin), interleukin-5 receptor a, lymphocyte receptor CD63, various glutamate receptor subtypes, and the syndecan family of heparan sulfate proteoglycans (3,5,6). This flexibility of interacting partners allows MDA-9/syntenin to participate in an assortment of biological functions, including receptor clustering (7), protein trafficking (8,9), synaptic transmission (3), activation of the transcription factor Sox4 (10), syndecan recycling through endosomal compartments (5), and cytoskeleton-membrane organization (11,12).…”

Extensions of PDZ domains as important structural and functional elements

“…The region of the target that interacts with PDZ is more commonly referred to as the PDZ binding motif (PBM). Many PDZ domains are also known to bind specific lipids (Zimmermann et al, 2002;Mortier et al, 2005;Yan et al, 2005;Wu et al, 2007).…”

Membrane Depolarization Increases Membrane PtdIns(4,5)P2 Levels through Mechanisms Involving PKC βII and PI4 Kinase

“…At the same time, PIP 2 is the phospholipid precursor of 3 second messengers: inositol trisphosphate (IP 3 ), diacylglycerol (DAG), and phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (4). In addition, it is now clear that phosphoinositides are not only precursors, but can also act as second messengers themselves and play a role in different important nuclear signaling events such as cell cycle progression, apoptosis, chromatin remodeling, transcriptional regulation, and mRNA processing (5,6). Finally, PIP 2 modulates the function of ion transporters and ion channels (7-9), including potassium channels (i.e.…”