Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over
100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate
each substrate, and why was it evolutionarily favorable for GSK3 to assume such a
large responsibility? GSK3 must be particularly adaptable for incorporating new substrates
into its repertoire, and we discuss the distinct properties of GSK3 that may contribute
to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms
regulating GSK3 (predominantly post-translational modifications, substrate priming,
cellular trafficking, protein complexes) have been reviewed previously, so here we
focus on newly identified complexities in these mechanisms, how each of these regulatory
mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate,
and how these mechanisms may have contributed to its adaptability as new substrates
evolved. The current understanding of the mechanisms regulating GSK3 is reviewed,
as are emerging topics in the actions of GSK3, particularly its interactions with
receptors and receptor-coupled signal transduction events, and differential actions
and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic
of GSK3 is its involvement in many prevalent disorders, including psychiatric and
neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility
of targeting GSK3 therapeutically, and provide an update of its involvement in the
etiology and treatment of several disorders.