BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

The tumor suppressive function of PTEN is exerted within 2 different cellular compartments. In the cytosol-membrane, it negatively regulates PI3K-AKT pathway through the de-phosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), therefore blocking one of the major signaling transduction...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2015-04, Vol.14 (7), p.973-979
Main Authors: Morotti, Alessandro, Panuzzo, Cristina, Crivellaro, Sabrina, Carrà, Giovanna, Fava, Carmen, Guerrasio, Angelo, Pandolfi, Pier Paolo, Saglio, Giuseppe
Format: Article
Language:English
Subjects:
Animals
Casein Kinase II - metabolism
Enzyme Activation
Fusion Proteins, bcr-abl - physiology
Humans
Mice
NIH 3T3 Cells
Phosphatidylinositol Phosphates - metabolism
Phosphorylation
Protein Processing, Post-Translational
PTEN Phosphohydrolase - metabolism
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Summary:The tumor suppressive function of PTEN is exerted within 2 different cellular compartments. In the cytosol-membrane, it negatively regulates PI3K-AKT pathway through the de-phosphorylation of phosphatidylinositol (3,4,5)-triphosphate (PIP3), therefore blocking one of the major signaling transduction pathways in tumorigenesis. In the nucleus, PTEN controls genomic stability and cellular proliferation through phosphatase independent mechanisms. Importantly, impairments in PTEN cellular compartmentalization, changes in protein levels and post-transductional modifications affect PTEN tumor suppressive functions. Targeting mechanisms that inactivate PTEN promotes apoptosis induction of cancer cells, without affecting normal cells, with appealing therapeutic implications. Recently, we have shown that BCR-ABL promotes PTEN nuclear exclusion by favoring HAUSP mediated PTEN de-ubiquitination in Chronic Myeloid Leukemia. Here, we show that nuclear exclusion of PTEN is associated with PTEN inactivation in the cytoplasm of CML cells. In particular, BCR-ABL promotes Casein Kinase II-mediated PTEN tail phosphorylation with consequent inhibition of the phosphatase activity toward PIP3. Targeting Casein Kinase II promotes PTEN reactivation with apoptosis induction. We therefore propose a novel BCR-ABL/CKII/PTEN pathway as a potential target to achieve synthetic lethality with tyrosine kinase inhibitors.
ISSN:1538-4101
1551-4005
DOI:10.1080/15384101.2015.1006970