Schneider Philipp, Bayo-Fina Juan Miguel, Singh Rajeev, Kumar Dhanyamraju Pavan, Holz Philipp, Baier Aninja, Fendrich Volker, Ramaswamy Annette, Baumeister Stefan, Martinez Elisabeth D, Lauth Matthias
Department of Medicine, Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Hans-Meerwein-Street 3, 35043 Marburg, Germany.
Department of Pharmacology, UT Southwestern Medical Center, 6000 Harry Hines boulevard, Dallas, Texas 75390-8593, USA.
Nat Commun. 2015 Aug 27;6:8023. doi: 10.1038/ncomms9023.
The Down syndrome-associated DYRK1A kinase has been reported as a stimulator of the developmentally important Hedgehog (Hh) pathway, but cells from Down syndrome patients paradoxically display reduced Hh signalling activity. Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. In contrast, in vivo and in vitro experiments reveal that DYRK1A kinase can also function as an inhibitor of endogenous Hh signalling by negatively regulating ABLIM proteins, the actin cytoskeleton and the transcriptional co-activator MKL1 (MAL). As a final effector of the DYRK1A-ABLIM-actin-MKL1 sequence, we identify the MKL1 interactor Jumonji domain demethylase 1A (JMJD1A) as a novel Hh pathway component stabilizing the GLI1 protein in a demethylase-independent manner. Furthermore, a Jumonji-specific small-molecule antagonist represents a novel and powerful inhibitor of Hh signal transduction by inducing GLI1 protein degradation in vitro and in vivo.
唐氏综合征相关的DYRK1A激酶已被报道为对发育至关重要的Hedgehog（Hh）信号通路的刺激因子，但唐氏综合征患者的细胞却反常地表现出Hh信号活性降低。我们发现，DYRK1A通过磷酸化一般核定位簇来刺激GLI转录因子活性。相反，体内和体外实验表明，DYRK1A激酶还可通过负向调节ABLIM蛋白、肌动蛋白细胞骨架和转录共激活因子MKL1（MAL），作为内源性Hh信号的抑制剂发挥作用。作为DYRK1A-ABLIM-肌动蛋白-MKL1序列的最终效应物，我们确定MKL1相互作用蛋白Jumonji结构域去甲基化酶1A（JMJD1A）是一种新型Hh信号通路成分，它以一种不依赖去甲基化酶的方式稳定GLI1蛋白。此外，一种Jumonji特异性小分子拮抗剂通过在体内外诱导GLI1蛋白降解，代表了一种新型且强大的Hh信号转导抑制剂。
