| Popis: |
Protein Phosphatase 2A (PP2A) is a major cellular serine-threonine phosphatase that directly regulates many diverse and essential signaling pathways. PP2A is a heterotrimeric enzyme composed of a scaffolding A-subunit, catalytic C-subunit, and one of several candidate regulatory B-subunits. Study of PP2A in human cancer has established its role as a tumor suppressor whose functions to maintain cell homeostasis are disrupted during cancer pathogenesis. A-alpha is the predominant isoform of the PP2A scaffolding A-subunit and is encoded by the gene PPP2R1A. Analysis of genomic data from human tumors revealed recurrent somatic mutations that cluster to key interaction points of the A-alpha subunit with its regulatory B-subunits and impair the assembly of complete PP2A holoenzymes. Of note, uterine endometrial carcinomas (EMCA) accounted for nearly 50% of the identified mutations. A subset of mutations, P179R/L/T and S256F/Y, were further identified as uniquely specific to the high-grade subtypes of EMCA, serous endometrial carcinoma and endometrial carcinosarcoma, occurring almost exclusively in these cancer types. To date, the role of these mutations in endometrial tumorigenesis and oncogenic signaling has not been fully elucidated. However, their striking disease specificity, occurrence in multiple EMCA patients, and location at structurally important sites within the A-alpha protein, suggest an impairment of PP2A’s biological activity in a manner that is directly advantageous to high-grade endometrial carcinoma development. The works presented here have characterized the impact of PPP2R1A P179R mutation on canonical PP2A tumor suppressive function. P179R represents the most frequent missense mutation of those that are reoccurring and disease-specific for high-grade EMCA. Described herein are structural and biochemical investigative works that enumerate the structural disturbance induced by proline-to-arginine substitution at the P179 locus, which alters the A-alpha protein’s stable conformations, and impedes interaction with PP2A catalytic and regulatory subunits. Cells harboring the P179R mutant isoform thus have significant disruption of PP2A and impaired negative regulation of pro-oncogenic pathways. This appears to include a novel role for PP2A in the reprogramming of cell identity through modulation of transcriptional programs relating to epithelial-mesenchymal identity and cancer stem cell identity. PP2A’s functional status correlated with the tumor initiating potential of cells, which is an essential biological property for primary tumor growth and metastasis initiation. Altogether, this body of research establishes a foundational understanding of the disease-driving mechanism of a recurrent PP2A A-alpha mutation, and how its dysregulation of molecular events contributes to endometrial carcinoma disease pathogenesis and progression. |
