A Chemical-Genetic Approach Reveals the Distinct Roles of GSK3? and GSK3? in Regulating Embryonic Stem Cell Fate.

ABSTRACT: Glycogen synthase kinase 3 (GSK3) plays a central role in diverse cellular processes. GSK3 has two mammalian isozymes, GSK3? and GSK3?, whose functions remain ill-defined because of a lack of inhibitors that can distinguish between the two highly homologous isozymes. Here, we show that GSK3? and GSK3? can be selectively inhibited in mouse embryonic stem cells (ESCs) using a chemical-genetic approach. Selective inhibition of GSK3? is sufficient to maintain mouse ESC self-renewal, whereas GSK3? inhibition promotes mouse ESC differentiation toward neural lineages. Genome-wide transcriptional analysis reveals that GSK3? and GSK3? have distinct sets of downstream targets. Furthermore, selective inhibition of individual GSK3 isozymes yields distinct phenotypes from gene deletion, highlighting the power of the chemical-genetic approach in dissecting kinase catalytic functions from the protein's scaffolding functions. Our study opens new avenues for defining GSK3 isozyme-specific functions in various cellular processes.

SUBMITTER: Chen X 

PROVIDER: S-EPMC5851779 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature