The Pkc1p kinase controls a highly-conserved cell wall integrity signalling pathway that regulates functions essential for growth and the integrity of proliferating cells (6, 7, 8). This pathway consists of a cascade of phosphorylation reactions initiated with the activation of Pkc1p (1, 9). Pkc1p then activates a basic three-protein kinase module involving an integration of the MEK-kinase Bck1p (10, 11), the redundant MEK-kinases Mkk1p and Mkk2p (12), and the MAP kinase Slt2p (13, 6). Strains disrupted for any of these protein kinases lose osmotic stability, especially at 37 C, such that the cells are viable only in the presence of sorbitol (or some other osmotic stabilizer), suggesting that the lysis is due to lack of cell wall integrity (8, 14).

Protein kinase C (PKC) is conserved throughout eukaryotes, and is highly regulated for both catalytic activity and intracellular localization (15). PKCs contain conserved regulatory motifs known as C1, C2, and HR1 domains, all of which are present in Pkc1p, the single isozyme present in S. cerevisiae (15). Pkc1p localizes to sites of polarized growth, consistent with its function in maintaining cell wall integrity, with the HR1 domain targeting it to the bud tip and the C1 domain targeting Pkc1p to the cell periphery (15). Deletion of the HR1 domain results in Pkc1p localization to the mitotic spindle with the C2 domain being responsible for this targeting (15). Pck1p activity is required for its localization to the bud neck, which also depends on the integrity of the septin ring (15). Pkc1p can also accumulate in the nucleus, and contains nuclear localization signals, as well as a nuclear exit signal (15). Therefore, it has been proposed that Pkc1p shuttles in and out of the nucleus and consequently has access to nuclear substrates (15). The nuclear and spindle localization of Pkc1p may provide a molecular explanation for previous observations suggesting a role for Pkc1p in regulating microtubule function (15).

Cercosporamide, a broad-spectrum natural antifungal compound, is a selective and highly potent fungal Pkc1p kinase inhibitor. Cells with reduced Pkc1p activity become hypersensitive to cercosporamide, and this sensitivity can be suppressed under high-osmotic growth conditions (7).

Last updated: 2005-03-22