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Oligopeptide Competition Assay for Phosphorylation Site Determination
Published on: May 18, 2017
Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation
Kun-yong Kim1, Ahmi Baek, Ji-Eun Hwang
1Department of Life Science, Research Center for Women's Diseases, Sookmyung Women's University, Seoul, Korea.
Abstract:
Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56gamma was directly phosphorylated by AMPK at Ser(298) and Ser(336), leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr(307). We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A.
Insights
Adiponectin, a protein linked to lower cancer risk, inhibits breast cancer cell invasion. It activates protein phosphatase 2A (PP2A), a tumor suppressor, by influencing its B56gamma subunit.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Low serum adiponectin levels are associated with increased risk for multiple cancers.
- Adiponectin is known to inhibit breast cancer cell proliferation and metastasis, but the specific molecular pathways are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which adiponectin suppresses breast cancer cell invasiveness.
- To investigate the role of AMP-activated protein kinase (AMPK) and protein phosphatase 2A (PP2A) in adiponectin's anti-cancer effects.
Main Methods:
- Utilized MDA-MB-231 breast cancer cells to study adiponectin signaling.
- Investigated the phosphorylation of PP2A's B56gamma subunit by AMPK.
- Assessed PP2A activity and AKT phosphorylation.
- Measured adiponectin and PP2A activity levels in breast cancer patient samples.
Main Results:
- Adiponectin activation of AMPK led to decreased invasiveness in MDA-MB-231 cells.
- AMPK directly phosphorylated B56gamma at Ser(298) and Ser(336), enhancing PP2A activity.
- This process involved the dephosphorylation of PP2Ac at Tyr(307).
- Breast cancer patients exhibited lower blood adiponectin and tissue PP2A activity.
- Direct adiponectin administration increased tumor tissue PP2A activity.
Conclusions:
- Adiponectin negatively regulates breast cancer cell invasiveness via the AMPK/PP2A pathway.
- Adiponectin activates the tumor suppressor PP2A, reducing cancer cell metastasis.
- These findings highlight adiponectin as a potential therapeutic target in breast cancer treatment.
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