Cdc37 Promotes the Stability of Protein Kinases Cdc28 and Cak1

Abstract

In the budding yeast Saccharomyces cerevisiae, Cdc37 is required for the productive formation of Cdc28-cyclin complexes. The cdc37-1 mutant arrests at Start with low levels of Cdc28 protein, which is predominantly unphosphorylated at Thr169, fails to bind cyclin, and has little protein kinase activity. We show here that Cdc28 and not cyclin is specifically defective in the cdc37-1 mutant and that Cdc37 likely does not act as an assembly factor for Cdc28-cyclin complex formation. We have also found that the levels and activity of the protein kinase Cak1 are significantly reduced in the cdc37-1 mutant. Pulse-chase analysis indicates that Cdc28 and Cak1 proteins are both destabilized when Cdc37 function is absent during but not after translation. In addition, Cdc37 promotes the production of Cak1, but not that of Cdc28, when coexpressed in insect cells. We conclude that budding yeast Cdc37, like its higher eukaryotic homologs, promotes the physical integrity of multiple protein kinases, perhaps by virtue of a cotranslational role in protein folding.

The mechanism of cell cycle regulation by v-Src

“…p16 binds to CAK but does not prevent it from phosphorylating CDK2 (Nishiwaki et al, 2000). Activation of S. cerevisiae CAK (Cak1) requires the chaperone Cdc37 (Farrell and Morgan, 2000) and in S. pombe, Cak1 activates CAK (Lee et al, 1999a). An enzyme similar to S. cerevisiae Cak1 has been identi®ed in mammalian cells (Kaldis and Solomon, 2000) therefore p16 may inhibit CAK by preventing the association of mammalian Cak1 with Cdc37 analogous to the way it inhibits CDK4 association with Cdc37.…”

Activity of Cdc2 and its interaction with the cyclin Cdc13 depend on the molecular chaperone Cdc37 inSchizosaccharomyces pombe

“…The majority of S. cerevisiae temperature-sensitive mutants of cdc37 arrest the cell cycle at Start (Dey et al, 1996;Farrell and Morgan, 2000;Gerber et al, 1995;Reed, 1980a;Reed, 1980b;Valay et al, 1995). This may reflect differences in cell-cycle control between the two yeasts: the major control point in S. cerevisiae is at Start within G1, whereas the fission yeast cell cycle is primarily regulated during G2.…”

“…In the S. cerevisiae mutant cdc37-1, the activity of the Cdc2 protein is reduced in part by aggregation of the Cdk into insoluble complexes (Farrell and Morgan, 2000). We tested whether this was happening in fission yeast cdc37 ts mutants as it would not affect overall cellular Cdc2 protein levels but would presumably reduce enzymatic activity.…”

“…Cdc37 clients are predominantly protein kinases and include cyclin-dependent kinases (Cdks) such as Cdk4 in mammalian cells (Dai et al, 1996;Lamphere et al, 1997;Stepanova et al, 1996) which regulates cell proliferation in G1, and Cdc28 in S. cerevisiae which is important for the G1-S and G2-M transitions (Farrell and Morgan, 2000;Gerber et al, 1995;Mort-Bontemps-Soret et al, 2002). Cdc37 also associates with non-kinase clients such as the androgen receptor (Rao et al, 2001).…”

The Hsp110 protein chaperone Sse1 is required for yeast cell wall integrity and morphogenesis

“…Multiple findings support the idea that the relationship between Hsp90 and Slt2 is unique. Hsp90 and the associated cochaperone Cdc37 are required for the stability of a majority of protein kinases, and loss of chaperone activity results in lowered client protein abundance (Farrell and Morgan 2000;Lee et al 2004;Hawle et al 2007;Mandal et al 2007). However, Slt2 stability is unaffected in numerous mutants with reduced Hsp90 activity (Piper et al 2006;Truman et al 2007).…”