TI - Regulation of mTORC1 signaling by Src kinase activity is Akt1-independent in RSV -transformed cells . AB - Increased activity of the Src tyrosine protein kinase that has been observed in a large number of human malignancies appears to be a promising target for drug therapy . In the present study , a critical role of the Src activity in the deregulation of mTOR signaling pathway in Rous sarcoma virus ( RSV ) -transformed hamster fibroblasts , H19 cells , was shown using these cells treated with the Src-specific inhibitor , SU6656 , and clones of fibroblasts expressing either the active Src or the dominant-negative Src kinase -dead mutant . Disruption of the Src kinase activity results in substantial reduction of the phosphorylation and activity of the Akt/protein kinase B ( PKB ) , phosphorylation of tuberin (TSC2) , mammalian target of rapamycin ( mTOR ) , S6K1 , ribosomal protein S6 , and eukaryotic initiation factor 4E -binding protein 4E-BP1 . The ectopic , active Akt1 that was expressed in Src-deficient cells significantly enhanced phosphorylation of TSC2 in these cells , but it failed to activate the inhibited components of the mTOR pathway that are downstream of TSC2 . The data indicate that the Src kinase activity is essential for the activity of mTOR -dependent signaling pathway and suggest that mTOR targets may be controlled by Src independently of Akt1/TSC2 cascade in cells expressing hyperactive Src protein . These observations might have an implication in drug resistance to mTOR inhibitor -based cancer therapy in certain cell types .