Cak1 Is Required for Kin28 Phosphorylation and Activation In Vivo

Espinoza, F. Hernán; Farrell, Alison; Nourse, Jamie P.; Chamberlin, Holly M.; Gileadi, O.; Morgan, David

doi:10.1128/mcb.18.11.6365

Cited by 63 publications

(35 citation statements)

References 61 publications

(94 reference statements)

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“…Thus, synthetic loss of viability on galactose between KIN28-T162A and hnt1⌬ accounts for synthetic loss of viability between cak1 and hnt1. Additionally, it is now possible to reconcile the observations that although cells with a single KIN28-T162A mutation are aphenotypic on glucose media (34), they are moderately temperature-sensitive on galactose media (33). Furthermore, in the experiment presented in Fig.…”

Section: Cak1 Is Not the Target Of Hnt1mentioning

confidence: 61%

“…To test whether mutation of Cak1, which is not only the CAK for Cdc28 (27)(28)(29) but also the CAK for Kin28 (33,34), also increases the cellular requirement for Hnt1, a strain bearing the cak1-civ1ts4 allele was disrupted for hnt1 to generate strain BY164. As with kin28-ts3, cak1 destabilization is synthetically less viable with Hnt1 deletion or ablation of Hnt1 enzymatic activity, and the double mutant phenotype is rescued by expression of rabbit Hint (Fig.…”

Section: Loss Of Hnt1 Enzymatic Activity Produces Synthetic Loss Of Vmentioning

confidence: 99%

“…If Cak1 were to be inhibited in hnt1 cells, the expected consequences would be reduction in Cdc28-activating phosphorylation (27)(28)(29) and reduction in Kin28 phosphorylation (33,34). To determine whether cells with a reduced level of phosphorylated Cdc28 are hyperdependent on Hnt1, we attempted to determine whether hnt1⌬ produces synthetic loss of viability with overexpression of Ptc2, a Cdc28 activation-loop phosphatase (63), and with temperaturesensitive mutation of cdc28.…”

Section: Cak1 Is Not the Target Of Hnt1mentioning

confidence: 99%

“…As shown in Fig. 4 (33,34), we reasoned that the basis for Cak1 dependence of hnt1 deletion strains might be that underphosphorylated Kin28 is hypersensitive to HNT1 status. The nonphosphorylatable KIN28-T162A allele is known to be intragenically synthetically less viable with kin28-ts16 and to be synthetically less viable with destabilizing mutations in tfb3 (34).…”

Section: Cak1 Is Not the Target Of Hnt1mentioning

confidence: 99%

“…In Saccharomyces cerevisiae, the CAK for Cdc28 is encoded by monomeric Cak1 (27)(28)(29), whereas the major RNA polymerase II C-terminal domain kinase of yeast is Kin28, which is TFIIHassociated (30,31) and lacks CAK activity (32). In addition to phosphorylating the activation loop of Cdc28, Cak1 phosphorylates the activation loop of Kin28 (33,34). Because the CAK, Cak1, and RNA polymerase II C-terminal domain kinase, Kin28, could both be considered orthologous to Cdk7 and because Kin28 is a substrate of Cak1, we considered the twohybrid and yeast genetic data (20) to be equivocal in identifying the direct target of Hnt1 regulation in yeast.…”

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confidence: 99%

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Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3

Bieganowski

Garrison

Hodawadekar

et al. 2002

Journal of Biological Chemistry

104

163

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The histidine triad superfamily of nucleotide hydrolases and nucleotide transferases consists of a branch of proteins related to Hint and Aprataxin, a branch of Fhitrelated hydrolases, and a branch of galactose-1-phosphate uridylyltransferase (GalT)-related transferases. Although substrates of Fhit and GalT are known and consequences of mutations in Aprataxin, Fhit, and GalT are known, good substrates had not been reported for any member of the Hint branch, and mutational consequences were unknown for Hint orthologs, which are the most ancient and widespread proteins in the Hint branch and in the histidine triad superfamily. Here we show that rabbit and yeast Hint hydrolyze the natural product adenosine-5-monophosphoramidate (AMPNH 2 ) in an active-site-dependent manner at second order rates exceeding 1,000,000 M ؊1 s ؊1 . Yeast strains constructed with specific loss of the Hnt1 active site fail to grow on galactose at elevated temperatures. Loss of Hnt1 enzyme activity also leads to hypersensitivity to mutations in Ccl1, Tfb3, and Kin28, which constitute the TFIIK kinase subcomplex of general transcription factor TFIIH and to mutations in Cak1, which phosphorylates Kin28. The target of Hnt1 regulation in this pathway was shown to be downstream of Cak1 and not to affect stability of Kin28 monomers. Functional complementation of all Hnt1 phenotypes was provided by rabbit Hint, which is only 22% identical to yeast Hnt1 but has very similar adenosine monophosphoramidase activity. Histidine triad (HIT)1 proteins are a superfamily of nucleotide-binding proteins named for a near C-terminal HXHXHXX motif (X is a hydrophobic amino acid) positioned at the ␣-phosphate of nucleotide substrates (1). The first branch of the superfamily is named for rabbit Hint, which had been purified as an abundant protein from cardiac cytosol by adenosine affinity chromatography (2) and shown to have homologs in all forms of life (1). Recently, Aprataxin, a gene located at 9p13 that is inactivated in ataxia with oculomotor apraxia, the second most common of the autosomal recessive ataxias, was identified as a member of the Hint branch of the HIT superfamily (3, 4). Human Fhit (5), which functions as a tumor suppressor protein in human (6 -9) and murine (10, 11) epithelial tissues, is the prototypical member of the second branch of the HIT superfamily. Fhit homologs have been found in fungi (12) and animals (13-16) and exhibit diadenosine polyphosphate hydrolase activity. A third branch of the HIT superfamily contains more distantly related nucleotide transferases including galactose-1-phosphate uridylyltransferase, which is the enzyme deficient in galactosemics (1), budding yeast diadenosine tetraphosphate phosphorylases ApaI and Apa2 (17), and adenylylsulfate:phosphate adenylyltransferase (18). Ironically, although Hint is the most ancient and widespread of the HIT proteins, reasonable Hint substrates remained unidentified, and the consequences of mutations in Hint or Hint orthologs were unknown (19).Recently, human Hint was identified as...

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Section: Cak1 Is Not the Target Of Hnt1mentioning

confidence: 61%

Section: Loss Of Hnt1 Enzymatic Activity Produces Synthetic Loss Of Vmentioning

confidence: 99%

Section: Cak1 Is Not the Target Of Hnt1mentioning

confidence: 99%

Section: Cak1 Is Not the Target Of Hnt1mentioning

confidence: 99%

mentioning

confidence: 99%

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Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3

Bieganowski

Garrison

Hodawadekar

et al. 2002

Journal of Biological Chemistry

104

163

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Cyclin‐dependent kinases: Masters of the eukaryotic universe

Pluta,

Studniarek,

Murphy

et al. 2023

WIREs RNA

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A family of structurally related cyclin‐dependent protein kinases (CDKs) drives many aspects of eukaryotic cell function. Much of the literature in this area has considered individual members of this family to act primarily either as regulators of the cell cycle, the context in which CDKs were first discovered, or as regulators of transcription. Until recently, CDK7 was the only clear example of a CDK that functions in both processes. However, new data points to several “cell‐cycle” CDKs having important roles in transcription and some “transcriptional” CDKs having cell cycle‐related targets. For example, novel functions in transcription have been demonstrated for the archetypal cell cycle regulator CDK1. The increasing evidence of the overlap between these two CDK types suggests that they might play a critical role in coordinating the two processes. Here we review the canonical functions of cell‐cycle and transcriptional CDKs, and provide an update on how these kinases collaborate to perform important cellular functions. We also provide a brief overview of how dysregulation of CDKs contributes to carcinogenesis, and possible treatment avenues.This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Processing > 3′ End Processing RNA Processing > Splicing Regulation/Alternative Splicing

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The cdk-activating kinase (CAK): from yeast to mammals

Kaldis

1999

CMLS, Cell. Mol. Life Sci.

206

189

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Cell cycle progression is regulated by cyclin-dependent kinases (cdks). The activity of cdks is tightly controlled by several mechanisms, including binding of subunits to cdks (cyclins and inhibitors), and phosphorylation events. This review focuses on the activating phosphorylation of cdks by an enzyme termed cdk-activating kinase (CAK). Two classes of CAKs have been identified: monomeric Cak1p from budding yeast and the p40MO15 (cdk7)/cyclin H/MAT1 complex from vertebrates. Cak1p is the physiological CAK in budding yeast and localizes to the cytoplasm. p40MO15(cdk7)/cyclin H/MAT1 localizes to the nucleus, is a subunit of the general transcription factor IIH and activates cdks as well as phosphorylates several components of the transcriptional machinery. Functions, substrate specificities, regulation, localization, effects on cdk structure and involvement in transcription are compared for Cak1p and p40MO15(cdk7).

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Cak1 Is Required for Kin28 Phosphorylation and Activation In Vivo

Cited by 63 publications

References 61 publications

Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3

Adenosine Monophosphoramidase Activity of Hint and Hnt1 Supports Function of Kin28, Ccl1, and Tfb3

Cyclin‐dependent kinases: Masters of the eukaryotic universe

The cdk-activating kinase (CAK): from yeast to mammals

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