PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner
Abstract Neurofibromin 2 (NF2, also known as merlin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. NF2 is also an actin-binding protein that functions in an intrinsic signaling network critical for actin dynamics. Although protein kinase A (PKA)-mediated NF2-serin (...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03325-9 |
| _version_ | 1818967098242629632 |
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| author | Ji-Eun Kim Duk-Shin Lee Tae-Hyun Kim Hana Park Min-Ju Kim Tae-Cheon Kang |
| author_facet | Ji-Eun Kim Duk-Shin Lee Tae-Hyun Kim Hana Park Min-Ju Kim Tae-Cheon Kang |
| author_sort | Ji-Eun Kim |
| collection | DOAJ |
| description | Abstract Neurofibromin 2 (NF2, also known as merlin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. NF2 is also an actin-binding protein that functions in an intrinsic signaling network critical for actin dynamics. Although protein kinase A (PKA)-mediated NF2-serin (S) 10 phosphorylation stabilizes filamentous actin (F-actin), the underlying mechanisms of NF2-S10 dephosphorylation and the role of NF2 in seizures have been elusive. Here, we demonstrate that pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) dephosphorylated NF2-S10 site as well as cofilin-S3 site. In addition, NF2-S10 dephosphorylation reversely regulated murine double minute-2 (Mdm2) and postsynaptic density 95 (PSD95) degradations in an activity-dependent manner, which increased seizure intensity and its progression in response to kainic acid (KA). In addition, NF2 knockdown facilitated seizure intensity and its progress through F-actin instability independent of cofilin-mediated actin dynamics. Therefore, we suggest that PLPP/CIN may be a potential therapeutic target for epileptogenesis and NF2-associated diseases. |
| first_indexed | 2024-12-20T13:43:23Z |
| format | Article |
| id | doaj.art-a5da058d3d7a486fa36a733dfaaa029b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-20T13:43:23Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a5da058d3d7a486fa36a733dfaaa029b2022-12-21T19:38:45ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111810.1038/s41419-020-03325-9PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent mannerJi-Eun Kim0Duk-Shin Lee1Tae-Hyun Kim2Hana Park3Min-Ju Kim4Tae-Cheon Kang5Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym UniversityDepartment of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym UniversityDepartment of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym UniversityDepartment of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym UniversityDepartment of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym UniversityDepartment of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym UniversityAbstract Neurofibromin 2 (NF2, also known as merlin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. NF2 is also an actin-binding protein that functions in an intrinsic signaling network critical for actin dynamics. Although protein kinase A (PKA)-mediated NF2-serin (S) 10 phosphorylation stabilizes filamentous actin (F-actin), the underlying mechanisms of NF2-S10 dephosphorylation and the role of NF2 in seizures have been elusive. Here, we demonstrate that pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) dephosphorylated NF2-S10 site as well as cofilin-S3 site. In addition, NF2-S10 dephosphorylation reversely regulated murine double minute-2 (Mdm2) and postsynaptic density 95 (PSD95) degradations in an activity-dependent manner, which increased seizure intensity and its progression in response to kainic acid (KA). In addition, NF2 knockdown facilitated seizure intensity and its progress through F-actin instability independent of cofilin-mediated actin dynamics. Therefore, we suggest that PLPP/CIN may be a potential therapeutic target for epileptogenesis and NF2-associated diseases.https://doi.org/10.1038/s41419-020-03325-9 |
| spellingShingle | Ji-Eun Kim Duk-Shin Lee Tae-Hyun Kim Hana Park Min-Ju Kim Tae-Cheon Kang PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner Cell Death and Disease |
| title | PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner |
| title_full | PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner |
| title_fullStr | PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner |
| title_full_unstemmed | PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner |
| title_short | PLPP/CIN-mediated NF2-serine 10 dephosphorylation regulates F-actin stability and Mdm2 degradation in an activity-dependent manner |
| title_sort | plpp cin mediated nf2 serine 10 dephosphorylation regulates f actin stability and mdm2 degradation in an activity dependent manner |
| url | https://doi.org/10.1038/s41419-020-03325-9 |
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