10.6084/m9.figshare.1292437.v3
Alessandro Morotti
Alessandro
Morotti
Cristina Panuzzo
Cristina
Panuzzo
Sabrina Crivellaro
Sabrina
Crivellaro
Giovanna CarrĂ
Giovanna
CarrĂ
Carmen Fava
Carmen
Fava
Angelo Guerrasio
Angelo
Guerrasio
Pier Paolo Pandolfi
Pier
Paolo Pandolfi
Giuseppe Saglio
Giuseppe
Saglio
BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation
Taylor & Francis Group
2015
casein kinase II
Chronic Myeloid Leukemia
PTEN
tumor suppressor
2015-10-09 15:47:33
Journal contribution
https://tandf.figshare.com/articles/journal_contribution/BCR_ABL_inactivates_cytosolic_PTEN_through_Casein_Kinase_II_mediated_tail_phosphorylation_/1292437
<p>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.</p>