Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal–Like Sequences for Nuclear Import Mediated by Major Vault Protein

Abstract

Although phosphatase and tensin homologue deleted on chromosome 10 (PTEN) localization in the nucleus and cytoplasm is established, the mechanism is unknown. PTEN is a tumor suppressor phosphatase that causes cell cycle arrest and/or apoptosis. Nuclear-cytoplasmic compartmentalization may be a novel mechanism in regulating these events. PTEN does not contain a traditional nuclear localization sequence (NLS); however, we identified putative NLS-like sequences, which we analyzed by site-directed mutagenesis and localization studies in MCF-7 cells. Two double site mutations exhibited nuclear localization defects. Furthermore, unlike wild-type PTEN, double NLS mutant PTEN did not interact with major vault protein (MVP), a previously hypothesized nuclear-cytoplasmic transport protein. We conclude that these two NLS-like sequences are required for PTEN nuclear import that is mediated by MVP. Further, we show that this MVP-mediated nuclear import is independent of PTEN phosphorylation and of the lipid and protein phosphatase activities of PTEN. (Cancer Res 2005; 65(10): 4108-16)

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…45 Our findings suggest that LAT, like CD247 and ZAP70, [41][42][43][44] plays a role in neurogenesis and that perturbation of this pathway may lead to neurodevelopmental phenotypes. They also provide an interesting example of the non-random organization of the genome 61 as gene dosage modification of (at least) one and five of the 9 and 28 genes mapping within the 220 kb BP2-BP3 and 600 kb BP4-BP5 intervals can influence the PTEN-antagonized (phosphatase and tensin homolog) PI3K/AKT and Ras/MAPK pathways: LAT, TAOK2, that encodes a PTEN-binding MAP kinase kinase kinase essential for dendrite morphogenesis, 62,63 MVP, the product of which interacts with PTEN and regulates its intracellular localization, 59,64,65 MAPK3, KCTD13, 37 and CDIPT (MIM: 605893) encoding an enzyme of the phosphatidylinositol synthesis pathway. Consistent with this view, the genes differentially expressed in cell lines of 16p11.2 600 kb BP4-BP5 carriers were enriched not only in pathways relevant to neurodevelopmental defects and ciliopathy but also in genes involved in phosphoinositide signaling.…”

Nuclear Localization of PTEN Is Regulated by Ca2+ through a Tyrosil Phosphorylation–Independent Conformational Modification in Major Vault Protein

“…MCF-7 breast cancer cells were cultured in high-glucose DMEM containing 10% fetal bovine serum (FBS), penicillin, and streptomycin. The MCF-7 Tet-Off cell line expressing wildtype PTEN (PTEN:WT) was generated and maintained as previously described (14). Vector expression was controlled with 2 Ag/mL tetracycline (Tet).…”

“…We have recently shown that PTEN has bipartite nuclear localization signal (NLS)-like sequences required for MVPmediated nuclear import of PTEN (14). MVP reportedly interacts with the C2 domain of PTEN through the EF hand-like motif in a Ca 2+ -dependent manner in HeLa cells (10).…”

A novel model to identify interaction partners of the PTEN tumor suppressor gene in human bladder cancer

“…While no direct function for MVP has been described, reports suggest nuclear translocation of target proteins such as PTEN [12], nuclear exclusion of chemotherapeutic drugs [13] and as a scaffold protein downstream of the EGFR [14]. The PTEN / MVP interaction has been previously observed in a yeast two hybrid system, and co-immunoprecipitations have been performed in human cancer cells [12].…”