Receptor-dependent and tyrosine phosphatase-mediated inhibition of GSK3 regulates cell fate choice.

Asymmetric body axis formation is central to metazoan development. Dictyostelium establishes an anterior/posterior axis utilizing seven-transmembrane cAMP morphogen receptors (CARs) and GSK3-mediated signal transductions that has a parallel with metazoan Wnt/Frizzled-GSK3 pathways. In Dictyostelium, GSK3 promotes posterior cell patterning but inhibits anterior cell differentiation. Tyrosine kinase ZAK1 mediates GSK3 activation. We now show that CAR4 regulates a tyrosine phosphatase that inhibits GSK3 activity. We have also identified essential phosphotyrosines in GSK3, confirmed their role in activated/deactivated regulation and cell fate decisions, and relate them to the predicted 3D structure of GSK3beta. CARs differentially regulate GSK3 activity by selectively activating a tyrosine phosphatase or kinase for pattern formation. The findings may provide a comparative understanding of CAR-GSK3 and Wnt/Frizzled-GSK3 pathways.