# Protein Phosphatase Control of AMPK Function

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $301,673

## Abstract

PROJECT SUMMARY
The goal of this proposed research is to reveal the negative regulator of AMPK and eventually target this pathway
to generate an efficient AMPK activator for treatment of metabolic syndromes. AMPK senses metabolic stress
and is a central mediator in maintaining metabolic homeostasis and energy balance. Thus, AMPK activation has
become an attractive target for treating metabolic syndromes, including diabetes and cancer. While it has been
demonstrated that AMPK activity is tightly regulated by reversible protein phosphorylation, and despite many
efforts to identify AMPK kinases, it is still unclear how AMPK is dephosphorylated or inactivated upon recovery
from metabolic stress. One of the main reasons for the limited progress in identifying an AMPK phosphatase is
because of the promiscuous activity of serine-threonine phosphatases and its specificity is governed by
associated proteins. We and others previously identified that PP2A family protein phosphatases are involved in
AMPK dephosphorylation. However, the PP2A phosphatase family contains hundreds of possible different
complexes. To identify a specific complex that directly dephosphorylates AMPK, using protein mass-
spectrometry analysis, we found that protein phosphatase 6 (PP6, a PP2A family phosphatase) regulatory
subunit SAPS3 is associated with AMPK. Furthermore, our preliminary data demonstrated that SAPS3/AMPK
binding is glucose responsive and required for AMPK dephosphorylation. To evaluate the role of SAPS3 in vivo,
we have generated a novel mouse model by flanking the gene encoding SAPS3, ppp6r3, with a loxP sequence
that allow us to develop tissue specific knock out of SAPS3. Using recently developed SAPS3 liver-specific
knockout mice, we found that deletion of SAPS3 increases AMPK phosphorylation in liver and displays
phenotypes similar to AMPK activation in regulation of metabolism and tumorigenesis. Therefore, we propose a
series of experiments in this application to address our central hypothesis that SAPS3-containing PP6
phosphatase complex dephosphorylates and inhibits AMPK activity, thereby regulating AMPK-mediated
functions. Three specific aims are proposed as follows: 1) elucidating molecular mechanisms underlying AMPK
inhibition by SAPS3-containing PP6 complex, 2) determining the biological function of SAPS3 in
metabolic/energy homeostasis in vivo via regulation of AMPK using SAPS3 liver specific knockout mice, 3)
examining the role of SAPS3 in tumorigenesis via regulation of AMPK in two mouse tumor models. These studies
will provide a solid mechanistic basis for AMPK signaling regulated by protein phosphatase and in vivo evidence
that AMPK-mediated biological functions are tightly controlled by protein phosphatase. Results from the
proposed research will also advance new therapeutic directions by targeting the SAPS3/AMPK interaction, which
could be an effective approach to activate AMPK for treating metabolic syndromes.

## Key facts

- **NIH application ID:** 9899273
- **Project number:** 5R01GM132142-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** MEI KONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,673
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899273

## Citation

> US National Institutes of Health, RePORTER application 9899273, Protein Phosphatase Control of AMPK Function (5R01GM132142-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899273. Licensed CC0.

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