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 (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.

• Authors: Ji-Eun Kim, Duk-Shin Lee, Tae-Hyun Kim, Hana Park, Min-Ju Kim, Tae-Cheon Kang
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 1 Pg. 37 (01 04 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33414453 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Neurofibromin 2
• Nf2 protein, mouse
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2
• Pdxp protein, mouse
• Phosphoprotein Phosphatases

Topics

• Actins (metabolism)
• Animals
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neurofibromin 2 (metabolism)
• Phosphoprotein Phosphatases (physiology)
• Phosphorylation
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Seizures (metabolism)