Crk1, a novel Cdc2-related protein kinase, is required for hyphal development and virulence in Candida albicans

Both mitogen-activated protein kinases and cyclin-dependent kinases play a role in hyphal development in Candida albicans. Using an oligonucleotide pr obe-based screen, we have isolated a new member of the Cdc2 kinase subfamil y, designated Crk1 (Cdc2-related kinase). The protein sequence of Crk1 is m ost similar to those of Saccharomyces cerevisiae Sgv1 and human Pkl1/Cdk9. In S. cerevisiae, CRK1 suppresses some, but not all, of the defects associa ted with an sgv1 mutant. Deleting both copies of CRK1 in C. albicans slows growth slightly but leads to a profound defect in hyphal development under all conditions examined. crk1/crk1 mutants are impaired in the induction of hypha-specific genes and are avirulent in mice. Consistent with this, ecto pic expression of the Crk1 kinase domain (CRK1N) promotes filamentous or in vasive growth in S. cerevisiae and hyphal development in C. albicans. The a ctivity of Crk1 in S. cerevisiae requires Flo8 but is independent of Ste12 and Phd1. Similarly, Crk1 promotes filamentation through a route independen t of Cph1 and Efg1 in C. albicans. RAS1(V13) can also activate filamentatio n in a cph1/cph1 efg1/efg1 double mutant. Interestingly, CRK1N produces flo rid hyphae in ras1/ras1 strains, while RAS1(V13) generates feeble hyphae in crk1/crk1 strains.