Glycogen synthase kinase-3 ? and ? (GSK-3?, ?) are serine/threonine kinases that regulate metabolic enzymes and transcription factors, which are responsible for coordinating processes such as glycogen synthesis and cell adhesion. GSK-3? activity is also required for nuclear activity of Rel dimers, which mediate an anti-apoptotic response to TNF? in mice. GSK-3 catalytic kinase activity is controlled through differential phosphorylation of serine/threonine residues, which have an inhibitory effect, and tyrosine residues, which have an activating effect. Growth factor stimulation of mammalian cells expressing GSK-3? and GSK-3? induces phosphorylation of Ser 21 and Ser 9, respectively through a phosphatidylinositol 3-kinase (PI 3-kinase)-protein kinase B (PKB) dependent pathway, thereby enhancing proliferative signals. Additionally, GSK-3 physically associates with cAMP-dependent protein kinase A (PKA), which phosphorylates Ser 21 of GSK-3? or Ser 9 of GSK-3? and inactivates both forms