8月6日,，國際知名學術期刊《PLoS Biology》在線發(fā)表了中科院上海生科院生化與細胞所張雷研究組、劉新垣研究組和趙允研究組合作完成的最新研究成果——“Par-1 regulates tissue growth by influencing hippo phosphorylate on status and hippo-salvador association”,。在這項工作中,，博士研究生黃宏齡等人發(fā)現(xiàn)了一個新的Hippo信號通路成員Par-1激酶，闡明了其在Hippo信號通路中負調(diào)控Hippo激酶活性的作用機制,，并初步揭示了這種調(diào)控機制的保守性,。
Hippo信號通路控制了脊椎動物以及非脊椎動物眾多發(fā)育過程中細胞的生長及器官的大小，其異常將會導致包括發(fā)育缺陷及腫瘤,、癌癥在內(nèi)的多種發(fā)育異常和生理性疾病,。在果蠅中，Hippo通路上游的信號經(jīng)過一系列激酶復合物的磷酸化級聯(lián)反應,，最終通過磷酸化下游的效應因子Yorkie,，使其滯留在胞質(zhì)內(nèi)，不能進入細胞核行使其轉(zhuǎn)錄激活功能,，從而實現(xiàn)對組織的生長調(diào)控,。黃宏齡等人通過一系列遺傳、分子和細胞生物學研究手段發(fā)現(xiàn),，Par-1與Hippo和支架蛋白Salvador相互作用,，并證實Par-1能通過調(diào)節(jié)Hippo Ser30位點磷酸化及 Hippo-Salvador復合物的穩(wěn)定性，從而負調(diào)節(jié)Hippo信號通路,。
由于Hippo通路在進化上是最為保守的信號通路之一,，果蠅中Hippo信號轉(zhuǎn)導機制的研究對深入理解哺乳動物中Hippo信號途徑的作用機制及其缺陷導致的相關癌癥的靶向治療具有十分重要的借鑒意義。
黃宏齡與王詩敏為本文的共同第一作者,，該項工作得到了浙江大學趙斌教授課題組的大力支持,，并獲得了國家科技部、國家基金委以及中國科學院（干細胞先導專項）的資助,。（生物谷Bioon.com）
doi:10.1371/journal.pbio.1001620
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Par-1 Regulates Tissue Growth by Influencing Hippo Phosphorylation Status and Hippo-Salvador Association
Huang H-L, Wang S, Yin M-X, Dong L, Wang C, et al
The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. Here, we reported the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevated Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminished Hpo target gene expression and reduced organ size. We demonstrated that par-1 functioned downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, we also found that Par-1 physically interacted with Hpo and Sav and regulated the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibited the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, we provided evidence that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, our findings identified Par-1 as a novel component of the Hpo signaling network.
