High impact information on CAK1

• Civ1 binds tightly to and phosphorylates Cdc28, thereby allowing its subsequent activation by the binding of a cyclin [1].
• Most Cdks require binding of a cyclin and phosphorylation by a Cdk-activating kinase (CAK) to be active [1].
• The CAK1 gene was essential for cell viability [2].
• Cak1 accounted for most CAK activity in yeast cell lysates, and its activity was constant throughout the cell cycle [2].
• Cdk7 is essential for mitosis and for in vivo Cdk-activating kinase activity [3].

Biological context of CAK1

• CAK1 encodes a protein kinase in Saccharomyces cerevisiae whose sole essential mitotic role is to activate the Cdc28p cyclin-dependent kinase by phosphorylation of threonine-169 in its activation loop [4].
• CAK1 also has several CDC28-independent functions that are unique to meiosis [5].
• Cak1 is required for the phosphorylation and activation of Cdc28, a major CDK involved in cell cycle control [6].
• The Cdk-activating kinase Cak1p promotes meiotic S phase through Ime2p [5].
• The work presented here demonstrates that CAK1 functions positively in the spore wall morphogenesis pathway [7].

Anatomical context of CAK1

• Cyclin-dependent kinases (cdks) coordinate progression through the eukaryotic cell cycle and require phosphorylation by a cdk-activating kinase (CAK) for full activity [8].

Associations of CAK1 with chemical compounds

• Our data show that Cak1p is required to activate Ime2p through a mechanism that requires threonine 242 and tyrosine 244 in Ime2p's activation loop [5].
• Two steps are essential for Cdk activation: binding of a cyclin and phosphorylation on a conserved threonine residue by the Cdk-activating kinase (CAK) [9].
• Cak1p lacks the highly conserved glycine loop motif (GXGXXG) that is found in the nucleotide binding fold of virtually all protein kinases and also lacks a number of conserved amino acids found at sites throughout the protein kinase core sequence [10].
• Similarly, Cak1p is insensitive to the ATP analog 5'-fluorosulfonylbenzoyladenosine, which inhibits most protein kinases through covalent modification of the invariant lysine [10].

Physical interactions of CAK1

• Activation of the Bur1-Bur2 cyclin-dependent kinase complex by Cak1 [11].
• Suppression is independent of the kinase activity of Cak1, suggesting that Cak1 may bind to the carboxyl terminus to serve a non-catalytic role in assembly and/or stabilization of active Cdc28 complexes [12].

Enzymatic interactions of CAK1

• We propose that Cdc28p is normally phosphorylated by Cak1p before it binds cyclin [9].
• Moreover, Cak1 directly phosphorylated Ctk1 in vitro [13].

Regulatory relationships of CAK1

• CAK1 promotes meiosis and spore formation in Saccharomyces cerevisiae in a CDC28-independent fashion [4].
• We conclude that Cak1 is required for the activating phosphorylation of Kin28 as well as that of Cdc28 [6].
• The CDK-activating kinase CAK1 can dosage suppress sporulation defects of smk1 MAP kinase mutants and is required for spore wall morphogenesis in Saccharomyces cerevisiae [7].
• Phosphorylation by Cak1 regulates the C-terminal domain kinase Ctk1 in Saccharomyces cerevisiae [13].

Other interactions of CAK1

• CAK1 was previously identified as a multicopy suppressor of a weakened smk1 mutant and shown to be required for spore wall assembly [4].
• Cak1 is required for Kin28 phosphorylation and activation in vivo [6].
• Consistent with Cak1p's role in activating Ime2p, cells lacking Cak1p are deficient in degrading Sic1p [5].
• We also found that mutants lacking CAK1 are blocked early in meiotic development, as they show substantial delays in premeiotic DNA synthesis and defects in the expression of sporulation-specific genes, including IME1 [4].
• Three high-copy suppressors of pbs2-3 osmosensitivity were identified: MSG5, CAK1, and TRX1 [14].

Analytical, diagnostic and therapeutic context of CAK1

• We have prepared phosphorylated cyclin-dependent protein kinase 2 (CDK2) for crystallization using the CDK-activating kinase 1 (CAK1) from Saccharomyces cerevisiae and have grown crystals using microseeding techniques [15].
• Furthermore, Cak1p contains no posttranslational modifications detectable by two-dimensional isoelectric focusing [16].
• We have found that Cak1p is dispersed throughout the cell as shown by immunofluorescence; biochemical subcellular fractionation confirmed that most of the Cak1p is found in the cytoplasm [16].

References