Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23.
Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23.
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DOI：
10.1186/1741-7007-12-12
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发表时间：
2014-02-14
期刊：
影响因子：
5.4
通讯作者：
Hsu T
中科院分区：
文献类型：
--
作者：
Ignesti M;Barraco M;Nallamothu G;Woolworth JA;Duchi S;Gargiulo G;Cavaliere V;Hsu T
果蝇异常翼盘(AWD)是一个高度保守的基因家族，与肿瘤转移抑制、代谢动态平衡和上皮形态发生有关。该家族中的哺乳动物成员Nm23蛋白的细胞功能尚未明确。以前的AWD基因分析揭示了它的内吞作用，这是控制不同信号通路的受体正确内化所必需的。在这项研究中，我们分析了AWD在发育过程中控制Notch信号的作用。为了研究AWD基因的功能，我们使用遗传镶嵌的方法来获得纯合的功能等位基因缺失的细胞。在AWD突变的滤泡细胞和翼盘细胞中，Notch在扩大的早期内小体中积累，导致Notch信号缺陷。我们的结果表明，在γ分泌酶介导的切割之前，AWD的功能是必需的，因为在AWD突变的毛囊细胞中过度表达具有结构性活性的Notch受体可以挽救信号。通过使用不同内体隔室的标记，我们证明了Notch受体在AWD突变毛囊细胞的早期内体中积累。活体翼盘的运输分析也表明，Notch在早期的内体中积累。重要的是，结构活性Rab5不能挽救AWD表型，这表明AWD是Rab5在内体成熟早期发挥作用所必需的。在这份报告中，我们论证了AWD通过其内吞作用对Notch信号转导是必不可少的。此外，我们确定了Notch信号转导需要AWD功能的胞内步骤，我们获得的证据表明AWD是Rab5功能所必需的。这些发现为这个重要基因家族的发育和病理生理功能提供了新的见解。
The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, the Nm23 proteins, has not yet been clearly defined. Previous awd genetic analyses unraveled its endocytic role that is required for proper internalization of receptors controlling different signaling pathways. In this study, we analyzed the role of Awd in controlling Notch signaling during development. To study the awd gene function we used genetic mosaic approaches to obtain cells homozygous for a loss of function allele. In awd mutant follicle cells and wing disc cells, Notch accumulates in enlarged early endosomes, resulting in defective Notch signaling. Our results demonstrate that awd function is required before γ-secretase mediated cleavage since over-expression of the constitutively active form of the Notch receptor in awd mutant follicle cells allows rescue of the signaling. By using markers of different endosomal compartments we show that Notch receptor accumulates in early endosomes in awd mutant follicle cells. A trafficking assay in living wing discs also shows that Notch accumulates in early endosomes. Importantly, constitutively active Rab5 cannot rescue the awd phenotype, suggesting that awd is required for Rab5 function in early endosome maturation. In this report we demonstrate that awd is essential for Notch signaling via its endocytic role. In addition, we identify the endocytic step at which Awd function is required for Notch signaling and we obtain evidence indicating that Awd is necessary for Rab5 function. These findings provide new insights into the developmental and pathophysiological function of this important gene family.
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影响因子：
3.6
作者：
Hsu, Tien
通讯作者：
Hsu, Tien
影响因子：
2.7
作者：
DEAROLF, CR;HERSPERGER, E;SHEARN, A
通讯作者：
SHEARN, A
影响因子：
6
作者：
Guijarro, Maria V.;Dahiya, Sonika;Hernando, Eva
通讯作者：
Hernando, Eva
DOI：
10.1111/j.1432-1033.1995.200_c.x
发表时间：
1995-11-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
ENGEL, M;VERON, M;WELTER, C
通讯作者：
WELTER, C
影响因子：
9.2
作者：
Furriols, M;Bray, S
通讯作者：
Bray, S