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JOURNAL ARTICLE
RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration.
Journal of Biological Chemistry 2000 November 25
We have studied the role of phosphatidylinositol 3-OH kinase (PI3K)-Akt signaling in transforming growth factor beta (TGFbeta)-mediated epithelial to mesenchymal transition (EMT). In NMuMG mammary epithelial cells, exogenous TGFbeta1 induced phosphorylation of Akt at Ser-473 and Akt in vitro kinase activity against GSK-3beta within 30 min. These responses were temporally correlated with delocalization of E-cadherin, ZO-1, and integrin beta(1) from cell junctions and the acquisition of spindle cell morphology. LY294002, an inhibitor of the p110 catalytic subunit of PI3K, and a dominant-negative mutant of Akt blocked the delocalization of ZO-1 induced by TGFbeta1, whereas transfection of constitutively active p110 induced loss of ZO-1 from tight junctions. In addition, LY294002 blocked TGFbeta-mediated C-terminal phosphorylation of Smad2. Consistent with these data, TGFbeta-induced p3TP-Lux and p(CAGA)(12)-Lux reporter activities were inhibited by LY294002 and transiently expressed dominant-negative p85 and Akt mutants in NMuMG and 4T1 cells. Dominant-negative RhoA inhibited TGFbeta-induced phosphorylation of Akt at Ser-473, whereas constitutively active RhoA increased the basal phosphorylation of Akt, suggesting that RhoA in involved in TGFbeta-induced EMT. Finally, LY294002 and neutralizing TGFbeta1 antibodies inhibited ligand-independent constitutively active Akt as well as basal and TGFbeta-stimulated migration in 4T1 and EMT6 breast tumor cells. Taken together, these data suggest that PI3K-Akt signaling is required for TGFbeta-induced transcriptional responses, EMT, and cell migration.
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