The role of Cdk7 in CAK function, a retro-retrospective

  1. J. Wade Harper and
  2. Stephen J. Elledge
  1. Verna and Marrs McLean Department of Biochemistry and Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, 77030 USA

This extract was created in the absence of an abstract.

Most transitions in the eukaryotic cell cycle are catalyzed by cyclin-dependent kinases (Cdks, CDKs), complexes formed between a member of the Cdk family of protein kinases and a regulatory cyclin subunit. CDKs are among the most highly regulated enzymes known: Their activities are controlled through multiple mechanisms that include cyclin association, positive and negative phosphorylation events, negative regulation through association with Cdk inhibitors (CKIs), and association with accessory proteins such as Cks/Suc1 (Fig. ) (reviewed in Morgan 1997). In addition to controlling Cdk activation, the cyclin subunit may also contribute to substrate specificity. These elaborate regulatory pathways reflect the critical roles of cyclin–kinases in the life of a cell; alterations that generate unregulated cyclin–kinase activity can promote improper proliferation that can result in developmental defects or proliferative diseases such as cancer (Sherr 1996).

 Multiple mechanisms regulate Cdk activity. Cdk activity is positively regulated (arrowheads) by association with cyclins, by phosphorylation on T161 by CAK, and by dephosphorylation by Cdc25 phosphatases. Cdk activity is negatively regulated by CKIs, Wee1-like kinases, and possibly by Kap1 phosphatase. The abundance of cyclins and some CKIs is regulated by transcriptional mechanisms and by ubiquitin-mediated proteolysis. The function of Cks1 is unknown but may involve substrate recognition.

The Cdk subunit alone is inactive and requires both association with a cyclin and phosphorylation on a conserved threonine residue (T161 in human Cdc2 and T160 in human Cdk2) for full activation (Gould et al. 1991; Desai et al. 1992; Solomon et al. 1992; Connell-Crowley et al. 1993). In the case of Cdk2, these two events account for an increase in activity of greater than seven orders of magnitude (Connell-Crowley et al. 1993; Russo 1997). Cyclin A promotes Cdk2 activation by inducing two major structural changes in the kinase that are likely to be …

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