論文 - 詳細
| RRC ID | 38193 |
|---|---|
| 著者 | Asaoka Y, Kanai F, Ichimura T, Tateishi K, Tanaka Y, Ohta M, Seto M, Tada M, Ijichi H, Ikenoue T, Kawabe T, Isobe T, Yaffe MB, Omata M. |
| タイトル | Identification of a suppressive mechanism for Hedgehog signaling through a novel interaction of Gli with 14-3-3. |
| ジャーナル | J Biol Chem |
| Abstract |
Gli transcription factors are central effectors of Hedgehog signaling in development and tumorigenesis. Using a tandem affinity purification (TAP) strategy and mass spectrometry, we have found that Gli1 interacts with 14-3-3epsilon, and that Gli2 and Gli3 also bind to 14-3-3epsilon through homologous sites. This interaction depends on their phosphorylation, and cAMP-dependent protein kinase (PKA), a known negative regulator of Hedgehog signaling serves as a responsible kinase. A Gli2 mutant engineered to eliminate this interaction exhibited increased transcriptional activity (2 approximately 3x). Transcriptional repression by 14-3-3 binding was also observed with Gli3, when its N-terminal repressor domain was deleted. The phosphorylation sites responsible for the binding to 14-3-3 are distinct from those required for proteolysis, the known mechanism for PKA-induced repression of Hh signaling. Our data propose a novel mechanism in which PKA down-regulates Hedgehog signaling by promoting the interaction between Gli and 14-3-3 as well as proteolysis. Given the certain neuronal or malignant disorders in human caused by the abnormality of 17p13 encompassing 14-3-3epsilon overlap with increased Hh signaling, the Gli-14-3-3 interaction may have pathological significance for those human diseases. |
| 巻・号 | 285(6) |
| ページ | 4185-4194 |
| 公開日 | 2010-2-5 |
| DOI | 10.1074/jbc.M109.038232 |
| PII | S0021-9258(20)81088-6 |
| PMID | 19996099 |
| PMC | PMC2823557 |
| MeSH | 14-3-3 Proteins / genetics 14-3-3 Proteins / metabolism* Amino Acid Substitution Animals Binding Sites Cell Line Cell Line, Tumor Cyclic AMP-Dependent Protein Kinases / metabolism HeLa Cells Hedgehog Proteins / genetics Hedgehog Proteins / metabolism* Humans Immunoblotting Immunoprecipitation Kruppel-Like Transcription Factors / genetics Kruppel-Like Transcription Factors / metabolism Mass Spectrometry Mice NIH 3T3 Cells Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism Phosphorylation Protein Binding RNA Interference Serine / genetics Serine / metabolism Signal Transduction* Transcription Factors / genetics Transcription Factors / metabolism* Transfection Zinc Finger Protein GLI1 Zinc Finger Protein Gli2 Zinc Finger Protein Gli3 |
| IF | 4.238 |
| 引用数 | 31 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | NIH3T3 |