title: Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia.
abstract: PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a bona fide dual lipid and protein phosphatase with cytoplasmic (Cy) and nuclear localization. PTEN nuclear exclusion has been associated with tumorigenesis. Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia (AML) and displays Cy localization in mutated nucleophosmin (NPMc+) AML. Here we show that NPM1 directly interacts with herpes virus-associated ubiquitin specific protease (HAUSP), which is known as a PTEN deubiquitinating enzyme. Strikingly, PTEN is aberrantly localized in AML carrying NPMc+. Mechanistically, NPM1 in the nucleus opposes HAUSP-mediated deubiquitination and this promotes the shuttle of PTEN to the cytoplasm. In the cytoplasm, NPMc+ prevents HAUSP from deubiquitinating PTEN, causing the latter to stay in the cytoplasm where it is polyubiquitinated and degraded. Our findings delineate a new NPM1-HAUSP molecular interaction controlling PTEN deubiquitination and trafficking.
authors.affiliation: Neuro-Oncoematology Unit, Santa Lucia Foundation, Rome, Italy. n.noguera@hsantalucia.it
authors.forename: N I
authors.initials: NI
authors.lastname: Noguera
authors.forename: M S
authors.initials: MS
authors.lastname: Song
authors.forename: M
authors.initials: M
authors.lastname: Divona
authors.forename: G
authors.initials: G
authors.lastname: Catalano
authors.forename: K L
authors.initials: KL
authors.lastname: Calvo
authors.forename: F
authors.initials: F
authors.lastname: García
authors.forename: T
authors.initials: T
authors.lastname: Ottone
authors.forename: F
authors.initials: F
authors.lastname: Florenzano
authors.forename: I
authors.initials: I
authors.lastname: Faraoni
authors.forename: L
authors.initials: L
authors.lastname: Battistini
authors.forename: E
authors.initials: E
authors.lastname: Colombo
authors.forename: S
authors.initials: S
authors.lastname: Amadori
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: F
authors.initials: F
authors.lastname: Lo-Coco
mesh_terms: D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D000090243:Nucleophosmin; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000378:metabolism*; D021381:Protein Transport; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7