Phospho PTEN mediated dephosphorylation of mitotic kinase PLK1 and Aurora Kinase A prevents aneuploidy and preserves genomic stability.

Autor: Ghosh, Ginia, Misra, Sandip, Ray, Rachayeeta, Chowdhury, Sougata Ghosh, Karmakar, Parimal
Zdroj: Medical Oncology; Apr2023, Vol. 40 Issue 4, p1-12, 12p
Abstrakt: PTEN, dual phosphatase tumor suppressor protein, is found to be frequently mutated in various cancers. Post-translational modification of PTEN is important for its sub-cellular localization and catalytic functions. But how these modifications affect cytological damage and aneuploidy is not studied in detail. We focus on the role of phosphatase activity along with C-terminal phosphorylation of PTEN in perspective of cytological damage like micronucleus, nuclear bud, and nuclear bridge formation. Our data suggest that wild-type PTEN, but not phospho-mutant PTEN significantly reduces cytological damage in PTEN null PC3 cells. In case of phosphatase-dead PTEN, cytological damage markers are increased during 24 h recovery after DNA damage. When we use phosphorylation and phosphatase-dead dual mutant PTEN, the extent of different cytological DNA damage parameters are similar to phosphatase-dead PTEN. We also find that both of those activities are essential for maintaining chromosome numbers. PTEN null cells exhibit significantly aberrant γ-tubulin pole formation during metaphase. Interestingly, we observed that p-PTEN localized to spindle poles along with PLK1 and Aurora Kinase A. Further depletion of phosphorylation and phosphatase activity of PTEN increases the expression of p-Aurora Kinase A (T288) and p-PLK1 (T210), compared to cells expressing wild-type PTEN. Again, wild-type PTEN but not phosphorylation-dead mutant is able to physically interact with PLK1 and Aurora Kinase A. Thus, our study suggests that the phosphorylation-dependent interaction of PTEN with PLK1 and Aurora Kinase A causes dephosphorylation of those mitotic kinases and by lowering their hyperphosphorylation status, PTEN prevents aberrant chromosome segregation in metaphase. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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