Abstract A44: PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells

PP2A holoenzyme complexes constitute the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits are highly conserved, a large number of B subunits share no homology, which determines PP2A substrate specificity and/or cellular localization. Although different PP2A complexes play distinct roles in cell signaling networks, PP2A has been defined only as a putative tumor suppressor, mostly based on loss-of-function studies using inhibitors (pharmacologic or biologic) for the highly conserved A or C subunit of PP2A. Many studies of specific pathways indicate that PP2A also possesses tumor-promoting function. We have reported an essential role of PR55α, a PP2A regulatory subunit, in supporting oncogenic phenotypes and in vivo tumorigenicity and metastasis of pancreatic cancer cells. In this study, we investigated a novel mechanism by which PR55α activates the YAP oncoprotein that plays an essential role in oncogenesis and metastasis of solid tumors including pancreatic cancer, resulting in its stabilization and nuclear retention. This mechanism involves PR55α’s inhibition of the MOB1-mediated LATS1/2 autoactivation, which otherwise would suppress YAP activation, and its direct activation of YAP itself. However, this mechanism does not involve the inhibition of upstream MST1/2 kinases and their subsequent T1079/T1041-phosphorylation of the LATS1/2 kinases. Furthermore, PR55α has the predominant effect on YAP activation, and the effect cannot be substituted by the depletion of either LATS1/2 or MOB1. Accordingly, PR55α is essential for YAP-promoted gene transcription, as well as for the anchorage-independent growth of cancer cells. In summary, current studies demonstrate a novel pancreatic cancer promoting mechanism through the PR55α-regulated PP2A. Citation Format: Ashley L. Hein, Nichole D. Brandquist, Caroline Y. Ouellette, Parthasarathy Seshacharyulu, Charles A. Enke, Michel M. Ouellette, Surinder K. Batra, Ying Yan. PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A44.