Fat-regulated adaptor protein Dlish binds the growth suppressor Expanded and controls its stability and ubiquitination
Fat-regulated adaptor protein Dlish binds the growth suppressor Expanded and controls its stability and ubiquitination
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脂肪调节衔接蛋白 Dlish 结合生长抑制因子 Expanded 并控制其稳定性和泛素化
DOI：
10.1073/pnas.1811891116
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Seth S. Blair
中科院分区：
文献类型：
--
作者：
Xing Wang;Yifei Zhang;Seth S. Blair
对于调节器官的生长和大小具有重要意义的是，细胞可以利用来自邻居的信息来修改细胞增殖的细胞内介质。河马细胞内通路是一种广泛应用于动物生长控制的纽带，但其受细胞外信号的调控尚不完全清楚。在这里，我们发现了一条调节果蝇器官大小的途径，这种途径是由跨膜受体--巨大的原钙粘附素脂肪触发的。我们发现脂肪调节的SH3结构域适配器蛋白DLISH与生长抑制因子Expanded结合并降低其稳定性，生长抑制因子Expanded是河马途径的已知调节因子。DLISH扩增的不稳定作用与先前建立的增加生长刺激蛋白DACH水平的途径平行。果蝇原钙粘附素脂肪通过河马途径控制器官大小，但与河马途径成分的生化联系仍不明确。我们以前发现了Dlish，一种SH3结构域蛋白，与Fat和XX型肌球蛋白Dachs物理上相互作用，并表明Fat对Dlish水平和活性的调节有助于限制Dachs介导的对河马通路活性的抑制。我们在这里描述了Fat和Dlish下游的一个平行的生长控制途径。用免疫沉淀和质谱仪寻找DLISH伙伴，发现DLISH与FERM结构域生长抑制因子扩展(Ex)结合；DLISH SH3结构域直接结合ExC末端的位点。我们进一步表明，在体内，DLISH减少了Ex的亚尖积累，并且Dlish的丢失阻止了由Fat丢失引起的Ex的不稳定。此外，DLISH还能与F-box E3泛素连接酶Slimm结合，促进SLimb介导的体外扩增泛素化。DLISH在体外和体内对Ex的作用都需要SLimb，强烈表明Dlish通过帮助将含有SLimb的E3泛素连接酶复合体招募到Ex来破坏Ex的稳定。
Significance To regulate the growth and size of organs, cells can use information from their neighbors to modify intracellular mediators of cell proliferation. The intracellular Hippo pathway is a widely utilized nexus for growth control in animals, but its regulation by extracellular signals is not fully understood. We here identify a pathway that regulates organ size in Drosophila, triggered by the transmembrane receptor, the giant protocadherin Fat. We show that the Fat-regulated SH3 domain adaptor protein Dlish binds to and reduces the stability of the growth suppressor Expanded, a known regulator of the Hippo pathway. The destabilization of Expanded by Dlish works in parallel to a previously established pathway in which Dlish increases levels of the growth-stimulating protein Dachs. The Drosophila protocadherin Fat controls organ size through the Hippo pathway, but the biochemical links to the Hippo pathway components are still poorly defined. We previously identified Dlish, an SH3 domain protein that physically interacts with Fat and the type XX myosin Dachs, and showed that Fat’s regulation of Dlish levels and activity helps limit Dachs-mediated inhibition of Hippo pathway activity. We here characterize a parallel growth control pathway downstream of Fat and Dlish. Using immunoprecipitation and mass spectrometry to search for Dlish partners, we find that Dlish binds the FERM domain growth repressor Expanded (Ex); Dlish SH3 domains directly bind sites in the Ex C terminus. We further show that, in vivo, Dlish reduces the subapical accumulation of Ex, and that loss of Dlish blocks the destabilization of Ex caused by loss of Fat. Moreover, Dlish can bind the F-box E3 ubiquitin ligase Slimb and promote Slimb-mediated ubiquitination of Expanded in vitro. Both the in vitro and in vivo effects of Dlish on Ex require Slimb, strongly suggesting that Dlish destabilizes Ex by helping recruit Slimb-containing E3 ubiquitin ligase complexes to Ex.
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影响因子：
11.8
作者：
Vrabioiu AM;Struhl G
通讯作者：
Struhl G
果蝇F-box蛋白FBXL7与原粘蛋白脂肪结合，并调节DACHS定位和河马信号传导。
影响因子：
7.7
作者：
Bosch JA;Sumabat TM;Hafezi Y;Pellock BJ;Gandhi KD;Hariharan IK
通讯作者：
Hariharan IK
影响因子：
7.2
作者：
Irvine KD;Harvey KF
通讯作者：
Harvey KF
影响因子：
4.6
作者：
B. McCartney;R. Kulikauskas;D. LaJeunesse;R. Fehon
通讯作者：
B. McCartney;R. Kulikauskas;D. LaJeunesse;R. Fehon
DOI：
10.1073/pnas.1315508111
发表时间：
2014-04
期刊：
Proceedings of the National Academy of Sciences
影响因子：
--
作者：
Paulo S. Ribeiro;M. Holder;D. Frith;A. Snijders;N. Tapon
通讯作者：
Paulo S. Ribeiro;M. Holder;D. Frith;A. Snijders;N. Tapon