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Growth Factor-Stimulated Phosphorylation of Akt and p70^S6K Is Differentially Inhibited by LY294002 and Wortmannin*

Department of Pediatrics, University of California, San Francisco, California 94143-0434

Address all correspondence and requests for reprints to: Saleh Adi, M.D., Department of Pediatrics, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, California 94143-0434. E-mail: adi{at}itsa.ucsf.edu

The phosphoinositide 3-kinase (PI3K) inhibitors, LY294002 (LY) and wortmannin (WM), are widely used to examine the role of PI3K in growth factor signaling. These compounds inhibit the kinase action of PI3K, thus preventing the accumulation of PI(3,4,5)P3 and PI(3,4)P2 (PIs) and subsequent phosphorylation and activation of the downstream effectors of PI3K, Akt and p70^S6K. The efficacy of these inhibitors has been demonstrated by measuring cellular levels of PIs or the kinase activity of immunoprecipitated PI3K. However, their effects on activation of Akt and p70^S6K, more widely used markers of PI3K activation, has not been formally tested. We have examined the effects of LY and WM on phosphorylation of Akt and p70^S6K by insulin-like growth factor-I, insulin, and platelet-derived growth factor in skeletal muscle cells. LY is much less effective in blocking the phosphorylation of Akt than p70^S6K; at concentrations which completely inhibit phosphorylation of p70^S6K, phosphorylation of Akt is only partially inhibited by LY. WM also inhibits IGF-I-stimulated phosphorylation of Akt and p70^S6K with unequal potency but is equally effective in blocking insulin-stimulated phosphorylation of these peptides. Our data demonstrate that inhibiting PI3K signaling through one of its downstream mediators (p70^S6K) may not indicate complete blockage of the PI3K pathway which may be signaling through an alternate downstream branch (Akt). These findings indicate that the efficacy of LY and WM inblocking PI3K-activation of Akt and p70^S6K must be tested within the context of every experiment, and that the results obtained with the use of these inhibitors must be interpreted according to their specific effects on the PI3K/Akt and PI3K/p70^S6K signaling pathways.

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