Identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1

Philipp Schneider, Juan Miguel Bayo-Fina, Rajeev Singh, Pavan Kumar Dhanyamraju, Philipp Holz, Aninja Baier, Volker Fendrich, Annette Ramaswamy, Stefan Baumeister, Elisabeth D. Martinez and Matthias Lauth ()
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Philipp Schneider: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology
Juan Miguel Bayo-Fina: UT Southwestern Medical Center
Rajeev Singh: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology
Pavan Kumar Dhanyamraju: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology
Philipp Holz: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology
Aninja Baier: Philipps University
Volker Fendrich: Philipps University
Annette Ramaswamy: Philipps University
Stefan Baumeister: Philipps University
Elisabeth D. Martinez: UT Southwestern Medical Center
Matthias Lauth: Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9023

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