" PP2A dephosphorylome governs cancer cell signalling and drug responses”.
|Date||13 February 2018|
|Time||10:00 - 11:00|
Group leader Cancer Cell Signaling
Research Professor of the Finnish Cancer Institute
Turku Centre for Biotechnology
We report comprehensive characterization of the tumor suppressor protein phosphatase 2A (PP2A)-regulated phosphoproteome. The data uncover PP2A-dependent coordinate regulation of cancer critical processes, as well as oncoproteins and tumor suppressors. We further discover paradigms relevant to phosphoregulation including unidirectionality of regulation of PP2A targets, as well as, intracellular cytoplasm-nuclear gradient of kinase- and phosphatase-dominant PP2A targets. This is exemplified by potent phosphorylation regulation of chromatin-modifying proteins by nuclear PP2A inhibitor protein SET.
Integration of this data with 7000 drug response profiles establishes PP2A activity as an overall determinant of cancer cell drug responses. The impact of this combined dataset is exemplified by characterization of PP2A inhibition as PARP and MEK inhibitor resistance mechanisms; validated in vivo by orally bioavailable small molecule PP2A reactivating molecules. Thus, this largest available PP2A knowledge base lays foundation for understanding the phosphatase landscape of cancer cell signalling, and the combinatorial use of emerging PP2A-targeted cancer therapies.