Thursday, September 18, 2025 9/18/2025

PR55-alpha controlled PP2A in the regulation of the Hippo/YAP pathway

Award Number: R01GM143329
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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PR55-alpha controlled PP2A in the regulation of the Hippo/YAP pathway - Abstract Pancreatic cancer (PC) is one of the most lethal cancers in the U.S. with a 5-year survival rate of 7%, which has essentially unchanged for the past 40 years. Despite extensive research, there are no effective targeted therapies for this disease, suggesting an insufficient understanding of oncogenic signaling networks in PC. While almost all of the signaling networks implicated in cancer rely on the cooperation of kinases and phosphatases to transduce signals promoting cancer, most efforts have only been put on the study of protein kinases in cancer while leaving protein phosphatases as a blind spot. PP2A is a family of heterotrimers that serve as the main source of Ser/Thr phosphatase activities in human cells, with each consisting of a scaffold subunit (Aα/β), a catalytic subunit (Cα/β), and one of many non-conserved regulatory (B) subunits (>27) that control the substrate specificities of PP2A complexes. Our preliminary studies identified PR55α, a regulatory subunit of PP2A, as an important new player in promoting malignant PC. In particular, our studies revealed that PR55 inhibits the MOB1/LATS auto-activation loop of the Hippo tumor suppression pathway, whose function is to induce the phosphorylation of YAP causing its cytoplasmic retention and proteasomal degradation. In line with the essential role of YAP signaling in Kras-driven PC development and progression, knockdown of PR55α impeded the anchorage-independent growth, tumorigenicity, and metastasis of PC cells. Our preliminary data also revealed that the stability of PR55α protein is negatively regulated by the tumor suppressor p53 and its target gene FBXL20, a substrate adaptor for the SCF (SKP1-CUL1-F-box protein) E3 ligase. Consistently, we observed that PR55α is elevated in PC specimens, where its expression correlates with poor patient survival. Based on these findings, we hypothesize that loss of p53 function results in the stabilization of PR55α protein, which, in turn, activates the YAP oncogenic signaling required for Kras-driving PC initiation and progression. We will test the hypothesis by three specific aims: Aim 1 to define the mechanism by which PR55α/PP2A promotes YAP activation and the significance of this cascade in oncogenesis and malignant potential of PC, Aim 2 to elucidate how p53 suppresses the level of PR55α, and Aim 3 to delineate the role of the PR55/YAP axis in pancreatic cancer development and progression in the KPC spontaneous mouse model. The work is innovative, as it will illuminate a critical pathway that promotes PC initiation and progression through PR55/PP2A activated YAP signaling, which is novel to both the PP2A field and the PC field. Successful completion of the proposed studies will yield an in-depth mechanistic understanding of the critical contribution of PR55/PP2A complex to the observed cooperation between Kras activation and the loss of the p53 tumor suppressor during PC development and progression. The acquired knowledge not only will improve the understanding of the role of PP2A in cancer but also will contribute to identifying novel therapeutic targets for improving the treatment of PC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Biomedical Research and Research Training	000	4	8/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $341,465 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Biomedical Research and Research Training	001	4	9/5/2024	SUPPLEMENT FOR EXPANSION	$34,465
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Biomedical Research and Research Training	000	4	8/30/2024	NON-COMPETING CONTINUATION	$307,000
														Subtotal = $341,465

Issue Date FY: 2023 ( Subtotal = $341,069 )
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Biomedical Research and Research Training	001	3	8/30/2023	NON-COMPETING CONTINUATION	$307,000
2023	2023	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Biomedical Research and Research Training	000	2	6/13/2023	SUPPLEMENT FOR EXPANSION	$34,069
														Subtotal = $341,069

Issue Date FY: 2022 ( Subtotal = $307,000 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Biomedical Research and Research Training	000	2	8/30/2022	NON-COMPETING CONTINUATION	$307,000
														Subtotal = $307,000

Issue Date FY: 2021 ( Subtotal = $306,167 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Biomedical Research and Research Training	000	1	8/3/2021	NEW	$306,167
														Subtotal = $306,167

Grand Total All Awards = $1,295,701

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PR55-alpha controlled PP2A in the regulation of the Hippo/YAP pathway

Award Number: R01GM143329

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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