Glycogen synthase kinase‐3 (GSK‐3) is a protein serine kinase implicated in the cellular response to insulin. The enzyme is the mammalian homologue of the zeste‐white3 (shaggy) homeotic gene of Drosophila melanogaster and has been implicated in the regulation of the c‐Jun/AP‐1 transcription factor. In mammals this protein serine kinase is encoded by two related genes termed GSK‐3 alpha and beta. Here, we demonstrate that these two proteins and the fruit fly protein are phosphorylated on tyrosine in vivo. Moreover, GSK‐3 beta activity and function are shown to be dependent on tyrosine phosphorylation. The modified tyrosine residue is conserved in all members of the GSK‐3 family and is equivalent to that required for activity by mitogen‐activated protein (MAP) kinases. However, unlike MAP kinases, GSK‐3 is highly phosphorylated on tyrosine and thus active in resting cells.
Extracellular cyclic AMP (cAMP) induces the formation of prespore cells in Dictyostelium but inhibits stalk cell formation. We have cloned gskA, which encodes the Dictyostelium homolog of glycogen synthase kinase 3 (GSK-3), and discovered that it is required for both cAMP effects. Disruption of gskA creates a mutant that aggregates but forms few spores and an abnormally high number of stalk cells. These stalk cells probably arise from an expanded prestalk B (pstB) cell population, which normally produces the basal disc of the fruiting body. In cultured mutant cells, cAMP neither inhibits pstB cell differentiation nor induces efficient prespore cell differentiation. We propose that cAMP acts through a common pathway that requires GSK-3 and determines the proportion of prespore and pstB cells.
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