MATRIX ADHESION AND RAS TRANSFORMATION BOTH ACTIVATE A PHOSPHOINOSITIDE 3-OH KINASE AND PROTEIN-KINASE B AKT CELLULAR-SURVIVAL PATHWAY/

Upon detachment from the extracellular matrix, epithelial cells enter into programmed cell death, a phenomenon known as anoikis, ensuring th at they are unable to survive in an inappropriate location, Activated ras oncogenes protect cells from this form of apoptosis, The nature of the survival signals activated by integrin engagement and usurped by oncogenic Pas are unknown: here we show that in both cases phosphoinos itide 3-OH kinase (PI 3-kinase), but not Raf, mediates this protection , acting through protein kinase B/Akt (PKB/Akt), Constitutively activa ted PI 3-kinase or PKB/Akt block anoikis, while inhibition of PI 3-kin ase abrogates protection by Pas, but not PKB/Akt, Inhibition of either PI 3-kinase or PKB/Akt induces apoptosis in adherent epithelial cells , Attachment of cells to matrix leads to rapid elevation of the levels of PI 3-kinase lipid products and PKB/Akt activity, both of which rem ain high in Pas-transformed cells even in suspension, PI 3-kinase acti ng through PKB/Akt is therefore implicated as a key mediator of the ab errant survival of Ras-transformed epithelial cells in the absence of attachment, and mediates matrix-induced survival of normal epithelial cells.