Glycogen Synthase Kinase 3 Is a Natural Activator of Mitogen-activated Protein Kinase/Extracellular Signal-regulated

Glycogen synthase kinase 3 (GSK3 ) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and insulin response. GSK3 has now been shown to induce activation of the mitogen-activated protein kinase kinase kinase MEKK1 and thereby to promote signaling by the stressactivated protein kinase pathway. GSK3 -binding protein blocked the activation of MEKK1 by GSK3 in human embryonic kidney 293 (HEK293) cells. Furthermore, co-immunoprecipitation analysis revealed a physical association between endogenous GSK3 and MEKK1 in HEK293 cells. Overexpression of axin1, a GSK3 -regulated scaffolding protein, did not affect the physical interaction between GSK3 and MEKK1 in transfected HEK293 cells. Exposure of cells to insulin inhibited the activation of MEKK1 by GSK3 , and this inhibitory effect of insulin was abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin. Furthermore, MEKK1 activity under either basal or UVor tumor necrosis factor -stimulated conditions was reduced in embryonic fibroblasts derived from GSK3 knockout mice compared with that in such cells from wild-type mice. Ectopic expression of GSK3 increased both basal and tumor necrosis factor -stimulated activities of MEKK1 in GSK3 / cells. Together, these observations suggest that GSK3 functions as a natural activator of MEKK1.