Glycogen synthase kinase 3 beta is a natural activator of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1)

Abstract

Glycogen synthase kinase 3beta (GSK3beta) is implicated in many biological events, including embryonic development, cell differentiation, apoptosis, and insulin response. GSK3beta has now been shown to induce activation of the mitogen-activated protein kinase kinase kinase MEKK1 and thereby to promote signaling by the stress-activated protein kinase pathway. GSK3beta-binding protein blocked the activation of MEKK1 by GSK3beta in human embryonic kidney 293 (HEK293) cells. Furthermore, co-immunoprecipitation analysis revealed a physical association between endogenous GSK3beta and MEKK1 in HEK293 cells. Overexpression of axin1, a GSK3beta-regulated scaffolding protein, did not affect the physical interaction between GSK3beta and MEKK1 in transfected HEK293 cells. Exposure of cells to insulin inhibited the activation of MEKK1 by GSK3beta, and this inhibitory effect of insulin was abolished by the phosphatidylinositol 3-kinase inhibitor wortmannin. Furthermore, MEKK1 activity under either basal or UV- or tumor necrosis factor alpha-stimulated conditions was reduced in embryonic fibroblasts derived from GSK3beta knockout mice compared with that in such cells from wild-type mice. Ectopic expression of GSK3beta increased both basal and tumor necrosis factor alpha-stimulated activities of HEKK1. in GSK3beta(-/-) cells. Together, these observations suggest that GSK3beta functions as a natural activator of MEKK1.