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

Cell Cycle. 2015;14(7):973-9. doi: 10.1080/15384101.2015.1006970.

Abstract

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.

Keywords: Chronic Myeloid Leukemia; PTEN; casein kinase II; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Casein Kinase II / metabolism*
  • Enzyme Activation
  • Fusion Proteins, bcr-abl / physiology*
  • Humans
  • Mice
  • NIH 3T3 Cells
  • PTEN Phosphohydrolase / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational*

Substances

  • Phosphatidylinositol Phosphates
  • phosphatidylinositol 3,4,5-triphosphate
  • Fusion Proteins, bcr-abl
  • Casein Kinase II
  • PTEN Phosphohydrolase
  • Pten protein, mouse