Regulation of molecular interaction between TGF-β and Wnt signalings

TGF-β 和 Wnt 信号传导之间分子相互作用的调节

• 批准号: 15390101
• 负责人: SHIBUYA Hiroshi
• 金额: $ 8.58万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390101/
• 关键词: Wnt signaling; NLK; Sox 11; HMG2L1; STAT3; TGF-β signaling; mcb-1; Atrogin1; E3リガーゼ; MFB-1; DAF7シグナル; DAF2; DAF-c; F-boxタンパク; 中胚葉誘導

TGF-β signaling regulates cell growth, differentiation, morphogenesis and apoptosis. TGF-β activated kinase 1 (TAK1) and Nemo-like kinase (NLK) function in Xenopus, Drosophila and C.elegans developments. Here we report that serine phosphorylation of STAT3 induced by TAK1-NLK cascade is essential for TGF-β-mediated mesoderm induction in Xenopus embryo. Depletion of TAK1, NLK or STAT3 blocks TGF-β-mediated mesoderm induction. Co-expression of NLK and STAT3 induces mesoderm by a mechanism that requires serine phosphorylation of STAT3. Activin activates NLK, which in turn directly phosphorylates STAT3. Moreover, depletion of either TAK1 or NLK inhibits endogenous serine phosphorylation of STAT3. These results provide the first evidence that TAK1-NLK-STAT3 cascade participates in TGF-β-mediated mesoderm induction.MAFbx/Atrogin-1 has been identified as a regulator for skeletal muscle atrophy, and encodes an F-box-type E3 ubiquitin ligase. However, little is known about how MAFbx/Atrogin-1 regulates cellular signaling. Here we identify and genetically characterize MFB-1, a MAFbx/Atrogin-1 homologue from Caenorhabditis elegans. The mfb-1 deletion mutant significantly enhanced the dauer constitutive (Daf-c) phenotype caused by mutations in the DAF-7/TrGF-β-like signaling pathway, but not the DAF-2/insulin receptor-like signaling pathway. Conversely, the Daf-c phenotypes of DAF-7 pathway mutants were partially suppressed by mfb-1 cDNA transgenes. Thus, MFB-1 acts genetically downstream in the DAF-7 pathway. A mfb-1 :: GFP fusion was found to be expressed in the nervous system, hypodermis and intestine, and overlapped expression of many DAF-7 pathway genes. We propose that MFB-1 is a novel F-box protein that negatively regulates dauer formation in concert with the DAF-7 signaling pathway in C.elegans.

TGF-β信号传导调节细胞生长、分化、形态发生和凋亡。TGF-β激活的激酶1（TAK 1）和Nemo-like激酶（NLK）在非洲爪蟾、果蝇和秀丽隐杆线虫发育中的功能。在这里，我们报告了由TAK 1-NLK级联诱导的STAT 3的丝氨酸磷酸化对于TGF-β介导的爪蟾胚胎中的中胚层诱导是必需的。TAK 1、NLK或STAT 3的消耗阻断TGF-β介导的中胚层诱导。NLK和STAT 3的共表达通过需要STAT 3的丝氨酸磷酸化的机制诱导中胚层。激活素激活NLK，NLK反过来直接磷酸化STAT 3。此外，TAK 1或NLK的耗竭抑制STAT 3的内源性丝氨酸磷酸化。这些结果为TAK 1-NLK-STAT 3级联反应参与TGF-β介导的中胚层诱导提供了第一个证据。MAFbx/Atrogin-1已被鉴定为骨骼肌萎缩的调节剂，并编码F-box-type E3泛素连接酶。然而，关于MAFbx/Atrogin-1如何调节细胞信号传导知之甚少。在这里，我们确定和遗传特性MFB-1，MAFbx/Atrogin-1同源秀丽隐杆线虫。mfb-1缺失突变体显著增强了dauer组成型（Daf-c）表型，该表型是由β 7/TrGF-β样信号传导通路中的突变引起的，但不是β 2/胰岛素受体样信号传导通路。相反，Daf-c表型的mfb-1的cDNA转基因的部分抑制的β-7途径突变体。因此，MFB-1在β-7通路的遗传下游起作用。A mfb-1：：发现GFP融合蛋白在神经系统、皮下组织和肠中表达，并且许多GFP-7途径基因重叠表达。我们建议，MFB-1是一种新的F-盒蛋白，负调控dauer形成与C. elegans中的p17 -7信号通路。

项目成果

Manipulation of alternative splicing by a newly developed inhibitor of Clks

• DOI: 10.1074/jbc.m314298200
• 发表时间: 2004-06-04
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Muraki, M;Ohkawara, B;Hagiwara, M
• 通讯作者: Hagiwara, M

Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling

• DOI: 10.1093/emboj/cdg605
• 发表时间: 2003-12-01
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Ishitani, T;Takaesu, G;Matsumoto, K
• 通讯作者: Matsumoto, K

Suzawa et al.: "Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade."Nature Cell Biol.. 5. 224-230 (2003)

Suzawa 等人：“细胞因子通过 TAK1/TAB1/NIK 级联抑制脂肪生成和 PPAR-γ 功能。”Nature Cell Biol.. 5. 224-230 (2003)

Negative regulation of Wnt signalling by HMG2L1, a novel NLK‐binding protein

• DOI: 10.1046/j.1365-2443.2003.00666.x
• 发表时间: 2003-08
• 期刊: Genes to Cells
• 影响因子: 2.1
• 作者: Misato Yamada;B. Ohkawara;N. Ichimura;Junko Hyodo‐Miura;S. Urushiyama;K. Shirakabe;H. Shibuya

Oishi et al.: "The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signaling pathway."Genes to Cells. 8. 645-654 (2003)

Oishi 等人：“受体酪氨酸激酶 Ror2 参与非经典 Wnt5a/JNK 信号通路。”基因到细胞。