The durum wheat TMKP1 gene encodes a MAP kinase phosphatase. When overexpressed in Saccharomyces cerevisiae, TMKP1 leads to salt stress tolerance (especially LiCl ), which is dependent on the phosphatase activity of the protein. The TMKP1-associated Li(+) resistance is restricted to a galactose-containing medium. Interestingly, this salt tolerance is abolished in the absence of one member of the yeast type 2C Ser/Thr protein phosphatase family (Ptc1) but not when other members such as Ptc2 or Ptc3 are lacking. Increased Li(+) tolerance is not mediated by regulation of the P-type ATPase Ena1, a major determinant for salt tolerance. In contrast, the effect of TMKP1 depends on Hal3 (a negative regulator of Ppz phosphatases) and on the presence of the high-affinity potassium transporters Trk1/Trk2. Tolerance to Li(+) is also abolished in cells lacking the aldose reductase Gre3, previously shown to be involved in the resistance to this cation. This study provides evidence that the wheat TMKP1 phosphatase is contributing to reduce the exacerbated lithium toxicity in galactose-grown cells, in a way that depends on the presence of the potassium Trk transporters.