The DAF-3 Smad protein antagonizes TGF-beta-related receptor signaling in the Caenorhabditis elegans dauer pathway
The DAF-3 Smad protein antagonizes TGF-beta-related receptor signaling in the Caenorhabditis elegans dauer pathway
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DOI：
10.1101/gad.11.20.2679
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发表时间：
1997-10-15
影响因子：
10.5
通讯作者：
Ruvkun, G
中科院分区：
文献类型：
--
作者：
Patterson, GI;Koweek, A;Ruvkun, G
转化生长因子-β超家族受体的信号通过转录激活靶基因的Smad蛋白传递到细胞核。在秀丽线虫中，转化生长因子-β相关途径的缺陷会导致达尔幼虫阶段可逆的发育停滞和代谢转移。Daf-3的零突变抑制了编码这种转化生长因子-β信号、其受体和相关的Smad信号转导蛋白的基因突变。DAF-3编码一种与哺乳动物DPC4关系最密切的Smad蛋白，在Dauer发育过程中重塑的许多组织中都有表达。DAF-4，这一途径中的II型转化生长因子-β受体，也在重塑的组织中表达。这些数据表明，来自感觉神经元的DAF-7信号作为贯穿全身的神经内分泌信号，直接调节在Dauer形成过程中重塑的组织的发育和代谢变化。一个全长的功能性DAF-3/GFP融合蛋白主要是细胞质的，这种定位独立于上游转化生长因子-β相关途径的活性。然而，这种融合蛋白与有丝分裂细胞中的染色体相关，表明DAF-3直接或间接地与DNA结合。DAF-3转基因也干扰Dauer的形成，可能是由于剂量效应。截短的DAF-3/GFP融合蛋白主要是核的，干扰Dauer的形成，这意味着DAF-3在核中发挥作用。这些数据表明，DAF-7信号转导拮抗或修饰细胞核中的DAF-3 Smad活性以诱导生殖发育；当DAF-7信号被禁用时，未修饰的DAF-3 Smad活性介导Dauer停滞及其相关的代谢变化。因此，DAF-3的独特之处在于，它是被转化生长因子-β途径拮抗而不是激活的。
Signals from TGF-beta superfamily receptors are transduced to the nucleus by Smad proteins, which transcriptionally activate target genes. In Caenorhabditis elegans, defects in a TGF-beta-related pathway cause a reversible developmental arrest and metabolic shift at the dauer larval stage. Null mutations in daf-3 suppress mutations in genes encoding this TGF-beta signal, its receptors, and associated Smad signal transduction proteins. daf-3 encodes a Smad protein that is most closely related to mammalian DPC4, and is expressed throughout development in many of the tissues that are remodeled during dauer development. DAF-4, the type II TGF-beta receptor in this pathway, is also expressed in remodeled tissues. These data suggest that the DAF-7 signal from sensory neurons acts as a neuroendocrine signal throughout the body to directly regulate developmental and metabolic shifts in tissues that are remodeled during dauer formation. A full-length functional DAF-3/GFP fusion protein is predominantly cytoplasmic, and this localization is independent of activity of the upstream TGF-beta-related pathway. However, this fusion protein is associated with chromosomes in mitotic cells, suggesting that DAF-3 binds DNA directly or indirectly. DAF-3 transgenes also interfere with dauer formation, perhaps attributable to a dosage effect. A truncated DAF-3/GFP fusion protein that is predominantly nuclear interferes with dauer formation, implying a role for DAF-3 in the nucleus. These data suggest that DAF-7 signal transduction antagonizes or modifies DAF-3 Smad activity in the nucleus to induce reproductive development; when DAF-7 signals are disabled, unmodified DAF-3 Smad activity mediates dauer arrest and its associated metabolic shift. Therefore, daf-3 is unique in that it is antagonized, rather than activated, by a TGF-beta pathway.