SCIENCE@home

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,P. Holz,A. Baier,V. Fendrich,A. Ramaswamy,S. Baumeister,Elisabeth D. Martinez,M. Lauth

Published 2015 in Nature Communications

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. The regulation of the Hedgehog (Hh) pathway by the kinase DYRK1A is controversial. Here the authors uncover a novel inhibitory activity of DYRK1A that functions to destabilize the Hh downstream transcription factor GLI1 by destabilizing actin and preventing the nuclear accumulation of protective MKL1/JMJD1A complexes.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-72 of 72 references · Page 1 of 1

CITED BY

Showing 1-62 of 62 citing papers · Page 1 of 1