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.
Highlights
The Down syndrome-associated dual-specificityregulated kinase 1A (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
The DYRK1A protein function is very sensitive to gene dosage and since Down syndrome patients have a higher DYRK1A expression due to the three DYRK1A copies in their genome, DYRK1A is considered constitutively overactive in their cells
DYRK1A levels are thought to contribute to the overall Down syndrome phenotype, an assumption that is in agreement with DYRK1Aoverexpressing transgenic mice showing deficits in memory and learning[2,3]
Summary
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. We find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. Certain morphological and cognitive deficits associated with Down spectrum could be ameliorated by the application of a synthetic Hh agonist[11,12], suggesting a general Hh pathway suppression in these patients This assumption is paradoxical as the DYRK1A kinase has been described as a stimulator of Hh pathway activity[13,14], which is expected to lead to an increase in Hh signalling. DYRK1A promotes the nuclear translocation of the GLI1 transcription factor through phosphorylation of clusters of general nuclear localization signals located in the N terminus
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have