Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STATprotein

Extracellular cAMP stimulates the rapid tyrosine phosphorylation and nuclea r translocation of the Dictyostelium STAT protein Dd-STATa. Here we show th at it also induces serine phosphorylation by GskA, a homologue of glycogen synthase kinase-3 (GSK-3). Tyrosine phosphorylation occurs within 10 s of s timulation, whereas serine phosphorylation takes 5 min, matching the kineti cs observed for the cAMP regulation of GskA, Phosphorylation by GskA enhanc es nuclear export of Dd-STATa. The phosphorylated region, however, is not i tself a nuclear export signal and we identify a region elsewhere in the pro tein that mediates nuclear export. These results suggest a biphasic regulat ion of Dd-STATa, in which extracellular cAMP initially directs nuclear impo rt and then, via GskA, promotes its subsequent export. It also raises the p ossibility of an analogous regulation of STAT nuclear export in higher euka ryotes.