We found in our present study that lithium (Li(+)) induced the expression of endogenous c-Ret, a tyrosine kinase receptor, in murine inner medullary collecting duct (mIMCD-3) cells. Delineation of the promoter region required for the effect of Li(+) identified a positive regulatory element within 180bp upstream of the transcription initiation site. This region contained three putative GC-rich Sp1 binding sites found to be essential for c-Ret induction by Li(+). The effect of Li(+) was mediated through glycogen synthase kinase 3β (GSK-3β) inhibition, although there was no biding site for T cell factor/lymphoid enhancer factor (TCF/LEF) in the 180bp. We found that Li(+) activated the mammalian target of rapamycin (mTOR) pathway via GSK-3β in these cells, and the effect of Li(+) to induce c-Ret was amenable to the inhibitory effect of the mTOR inhibitor, rapamycin. We also found that alterations in both cellular β-catenin levels and mTOR activities affected the effect of Li(+) on c-Ret transcription in a cooperative manner. In summary, our results show that Li(+) can induce c-Ret expression in mIMCD-3 cells through both β-catenin- and mTOR-dependent pathways downstream of GSK-3β inhibition, which act synergistically on the GC-rich Sp1 binding elements in the promoter region.