Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization
The family of forkhead box O (FoxO) transcription factors regulate cellular processes involved in glucose metabolism, stress resistance, DNA damage repair, and tumor suppression. FoxO transactivation activity is tightly regulated by a complex network of signaling pathways and post-translational modi...
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MDPI AG
2025-02-01
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| author | Adeline M. Luperchio Daniel J. Salamango |
| author_facet | Adeline M. Luperchio Daniel J. Salamango |
| author_sort | Adeline M. Luperchio |
| collection | DOAJ |
| description | The family of forkhead box O (FoxO) transcription factors regulate cellular processes involved in glucose metabolism, stress resistance, DNA damage repair, and tumor suppression. FoxO transactivation activity is tightly regulated by a complex network of signaling pathways and post-translational modifications. While it has been well established that phosphorylation promotes FoxO cytoplasmic retention and inactivation, the mechanism underlying dephosphorylation and nuclear translocation is less clear. Here, we investigate the role of protein phosphatase 2A (PP2A) in regulating this process. We demonstrate that PP2A and AMP-activated protein kinase (AMPK) combine to regulate nuclear translocation of multiple FoxO family members following inhibition of metabolic signaling or induction of oxidative stress. Moreover, chemical inhibitor studies indicate that nuclear accumulation of FoxO proteins occurs through inhibition of nuclear export as opposed to promoting nuclear import as previously speculated. Functional, genetic, and biochemical studies combine to identify the PP2A complexes that regulate FoxO nuclear translocation, and the binding motif required. Mutating the FoxO-PP2A interface to enhance or diminish PP2A binding alters nuclear translocation kinetics accordingly. Together, these studies shed light on the molecular mechanisms regulating FoxO nuclear translocation and provide insights into how FoxO regulation is integrated with metabolic and stress-related stimuli. |
| format | Article |
| id | doaj-art-00475e9876b44ba1b64fc7daba45462a |
| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-00475e9876b44ba1b64fc7daba45462a2025-08-20T02:53:19ZengMDPI AGCells2073-44092025-02-0114534210.3390/cells14050342Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor LocalizationAdeline M. Luperchio0Daniel J. Salamango1Department of Microbiology, Immunology, and Molecular Genetics, UT Health Science Center, San Antonio, TX 78229, USADepartment of Microbiology, Immunology, and Molecular Genetics, UT Health Science Center, San Antonio, TX 78229, USAThe family of forkhead box O (FoxO) transcription factors regulate cellular processes involved in glucose metabolism, stress resistance, DNA damage repair, and tumor suppression. FoxO transactivation activity is tightly regulated by a complex network of signaling pathways and post-translational modifications. While it has been well established that phosphorylation promotes FoxO cytoplasmic retention and inactivation, the mechanism underlying dephosphorylation and nuclear translocation is less clear. Here, we investigate the role of protein phosphatase 2A (PP2A) in regulating this process. We demonstrate that PP2A and AMP-activated protein kinase (AMPK) combine to regulate nuclear translocation of multiple FoxO family members following inhibition of metabolic signaling or induction of oxidative stress. Moreover, chemical inhibitor studies indicate that nuclear accumulation of FoxO proteins occurs through inhibition of nuclear export as opposed to promoting nuclear import as previously speculated. Functional, genetic, and biochemical studies combine to identify the PP2A complexes that regulate FoxO nuclear translocation, and the binding motif required. Mutating the FoxO-PP2A interface to enhance or diminish PP2A binding alters nuclear translocation kinetics accordingly. Together, these studies shed light on the molecular mechanisms regulating FoxO nuclear translocation and provide insights into how FoxO regulation is integrated with metabolic and stress-related stimuli.https://www.mdpi.com/2073-4409/14/5/342AKTFoxOPI3KPP2Asubcellular localizationtranscription factor |
| spellingShingle | Adeline M. Luperchio Daniel J. Salamango Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization Cells AKT FoxO PI3K PP2A subcellular localization transcription factor |
| title | Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization |
| title_full | Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization |
| title_fullStr | Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization |
| title_full_unstemmed | Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization |
| title_short | Defining the Protein Phosphatase 2A (PP2A) Subcomplexes That Regulate FoxO Transcription Factor Localization |
| title_sort | defining the protein phosphatase 2a pp2a subcomplexes that regulate foxo transcription factor localization |
| topic | AKT FoxO PI3K PP2A subcellular localization transcription factor |
| url | https://www.mdpi.com/2073-4409/14/5/342 |
| work_keys_str_mv | AT adelinemluperchio definingtheproteinphosphatase2app2asubcomplexesthatregulatefoxotranscriptionfactorlocalization AT danieljsalamango definingtheproteinphosphatase2app2asubcomplexesthatregulatefoxotranscriptionfactorlocalization |