論文 - 詳細
| RRC ID | 68385 |
|---|---|
| 著者 | Daimon E, Shibukawa Y, Thanasegaran S, Yamazaki N, Okamoto N. |
| タイトル | Macrothrombocytopenia of Takenouchi-Kosaki syndrome is ameliorated by CDC42 specific- and lipidation inhibitors in MEG-01 cells. |
| ジャーナル | Sci Rep |
| Abstract |
Macrothrombocytopenia is a common pathology of missense mutations in genes regulating actin dynamics. Takenouchi-Kosaki syndrome (TKS) harboring the c.191A > G, Tyr64Cys (Y64C) variant in Cdc42 exhibits a variety of clinical manifestations, including immunological and hematological anomalies. In the present study, we investigated the functional abnormalities of the Y64C mutant in HEK293 cells and elucidated the mechanism of macrothrombocytopenia, one of the symptoms of TKS patients, by monitoring the production of platelet-like particles (PLP) using MEG-01 cells. We found that the Y64C mutant was concentrated at the membrane compartment due to impaired binding to Rho-GDI and more active than the wild-type. The Y64C mutant also had lower association with its effectors Pak1/2 and N-WASP. Y64C mutant-expressing MEG-01 cells demonstrated short cytoplasmic protrusions with aberrant F-actin and microtubules, and reduced PLP production. This suggested that the Y64C mutant facilitates its activity and membrane localization, resulting in impaired F-actin dynamics for proplatelet extension, which is necessary for platelet production. Furthermore, such dysfunction was ameliorated by either suppression of Cdc42 activity or prenylation using chemical inhibitors. Our study may lead to pharmacological treatments for TKS patients. |
| 巻・号 | 11(1) |
| ページ | 17990 |
| 公開日 | 2021-9-9 |
| DOI | 10.1038/s41598-021-97478-y |
| PII | 10.1038/s41598-021-97478-y |
| PMID | 34504210 |
| PMC | PMC8429552 |
| MeSH | Actins / metabolism Alkyl and Aryl Transferases / antagonists & inhibitors Benzamides / pharmacology Blood Platelets / metabolism Cell Differentiation / drug effects Cell Line, Tumor Cell Membrane / metabolism HEK293 Cells Humans Megakaryocytes / drug effects* Megakaryocytes / metabolism* Mutation Protein Prenylation / drug effects Pyrazoles / pharmacology Signal Transduction / drug effects* Signal Transduction / genetics Sulfonamides / pharmacology Syndrome Thrombocytopenia / genetics Thrombocytopenia / metabolism* Thrombopoiesis / drug effects Thrombopoiesis / genetics Transfection Wiskott-Aldrich Syndrome Protein, Neuronal / metabolism cdc42 GTP-Binding Protein / antagonists & inhibitors* cdc42 GTP-Binding Protein / genetics cdc42 GTP-Binding Protein / metabolism* p21-Activated Kinases / metabolism rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism |
| IF | 3.998 |
| リソース情報 | |
| 遺伝子材料 | pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |