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First published online January 23, 2008
doi: 10.1242/10.1242/jcs.022459

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The nuclear affairs of PTEN

¹ Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
² Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
³ Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
⁴ Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
⁵ CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

View larger version (18K): [in this window] [in a new window]   Fig. 1. `Classic' PTEN pathway. Binding of ligand to membrane receptors activates PI3K. Activated PI3K phosphorylates PI(3,4)P (PIP2) to produce PI(3,4,5)P (PIP3). PIP3 recruits PDK1 to the plasma membrane. PDK1 phosphorylates and activates AKT, which regulates various cellular processes. The lipid phosphatase activity of cytoplasmic PTEN dephosphorylates PIP3, thereby decreasing PIP3 levels and increasing levels of PIP2, resulting in a concomitant decrease in AKT activity.

View larger version (71K): [in this window] [in a new window]   Fig. 2. Fluorescence microscopy of GFP-PTEN. Fluorescence microscopy of the human breast carcinoma cell line MCF-7 expressing exogenous wild-type PTEN tagged with green fluorescent protein. Fluorescent PTEN is noticeable in both the cytosolic and nuclear compartments in the cell. This micrograph demonstrates predominant nuclear localization.

View larger version (11K): [in this window] [in a new window]   Fig. 3. PTEN motifs involved in nucleo-cytoplasmic shuttling. PTEN consists primarily of two domains: the phosphatase and C-terminal domains. The phosphatase domain consists of residues 1-185, with its core motif (green) spanning residues 124-130. The C-terminal domain, residues 186-403, contains the lipid-binding C2 domain (residues 186-351), two PEST sequences involved in protein stability (residues 350-375 and 379-396) and a PDZ domain (shown in red), which is involved in protein-protein interactions. A putative cytoplasmic localization signal (CLS) spans residues 19-25. Four separate non-classical NLS motifs (NLS1 to NLS4) involved in binding to and the import by MVP have been localized to residues 10-14 (RNKRR), 160-164 (RTRDKK), 233-237 (RREDK) and 265-269 (KKDK). A mono-ubiquitylation site is present at K289 and regulates nuclear localization, as does a stretch of serine and threonine phosphorylation sites: S370, S380, T382, T383 and S385 (asterisks).

View larger version (66K): [in this window] [in a new window]   Fig. 4. Nuclear and cytoplasmic PTEN signaling. PTEN localizes to both the cytoplasm and the nucleus and shuttles between each by a variety of mechanisms. PTEN function is, at least in part, determined by its subcellular localization. The `classic' PTEN function is cytoplasmic and includes downregulation of AKT, which increases p27 levels and thereby leads to apoptosis. By contrast, nuclear PTEN has a variety of functions: downregulation of MAPK (ERK), leading to a decrease in cyclin D1 levels and G0-G1 arrest; upregulation of RAD51 levels and double-stranded-break repair; an interaction with CENP-C, which enhances centromere stability specifically and overall genomic stability; and apoptosis.