Doctoral dissertation (article) (G5)

Convergence of RAS and PP2A activities on chromatin repressor complexes




List of AuthorsSharma Mukund

PublisherUniversity of Turku

PlaceTurku

Publication year2024

ISBN 978-951-29-9624-7

eISBN978-951-29-9625-4

URLhttps://urn.fi/URN:ISBN:978-951-29-9625-4


Abstract

Protein Phosphatase 2A (PP2A) is a serine-threonine phosphatase and, through its de-phosphorylation activity, mostly downregulates signaling pathways, while RAS belongs to the family of small GTPase and activates various kinases resulting in the activation of cellular signaling. Decades back, it was shown that the inhibition of PP2A is a prerequisite for human cell transformation by the oncogenic RAS. Despite the mounting evidence highlighting RAS and PP2A-mediated protein phosphorylation to be of paramount significance in cancer biology, none of the studies have systematically addressed the cooperation between RAS and PP2A in regulating global protein phosphorylation.

My thesis focuses on the cooperation between the tumor suppressor PP2A and an oncogene RAS in regulating protein phosphorylation in cancer cells. By integrating the RAS- and PP2A-regulated phosphoproteomics data we found that the cellular proteome, is specifically enriched for RAS- and PP2A-regulated phosphosites on proteins involved in regulating various epigenetic modifications such as DNA methylation, histone methylation/acetylation and chromatin remodeling.

In the present work, I have validated the impact of the PP2A- and RAS-regulated phosphosites in the functional regulation of epigenetic proteins. Using multi-omics analysis, this study has further uncovered the opposing roles of RAS and PP2A in regulating gene expression. The present study has also compared the two nuclear inhibitors of PP2A, PME-1, and SET, and discovered the diversity of their roles in oncogenic transcription and DNA methylation. Collectively, this research work indicates that in cancer, RAS hyperactivity and PP2A inhibition converge on phosphorylation of epigenetic proteins and has a vital role in oncogenic transcription.


Last updated on 2024-27-02 at 15:32