DOC_CKS1_1

The cell division cycle is highly regulated by cyclin-dependent kinases (CDKs) that associate with and are activated by cyclins. Active cyclin-CDK complexes mediate protein phosphorylation, altering the activity and half-life of a wide range of substrates. The substrate specificity of cyclin-CDK complexes is established by the specific recognition of the substrate’s modification site (MOD_CDK_1) by CDK as well as docking of its cyclin-recognition site (DOC_CYCLIN_1) to cyclin. An additional motif-mediated interaction of CDK substrates with the Cyclin-dependent kinases regulatory subunit 1 (Cks1) (1QB3), which can simultaneously bind to CDK and its phosphorylated substrate, allows precise regulation of the binding affinities and multi-phosphorylation of the substrate.
Cks1, which was first identified in fission yeast (Hayles,1986), was shown to interact with and activate the G1S-specific Cln2-Cdc28 complex in yeast (Reynard,2000). Absence of Cks1 was shown to prevent both the G1 to S and G2 to M phase transitions (Reynard,2000; Tang,1993; Patra,1996), causing a restricted potential of cell division and influencing cell viability (Hindley,1987). Furthermore, Cks1 is involved in controlling the M to G1 phase transition as depletion of this protein in Xenopus results in a failure to activate the Anaphase Promoting Complex or Cyclosome (APC/C) by CDK-dependent hyper-phosphorylation of the Cdc27 subunit (Patra,1998). Overexpression of Cks1 in fission yeast and Xenopus caused an abnormal and reduced cell cycle with an elongated G2 phase and a decreased Cyclin B-Cdc2 activation, indicating that Cks1 functions both as a positive and negative regulator of the cell cycle (Hayles,2010; Patra,1996).
In mammals, two Cks1 paralogs (Cks1 and Cks2) with high sequence similarity are expressed. They appear to have overlapping functions as a knockout of either does not affect viability, while a double knockout is lethal in mice (Martinsson-Ahlzen,2008). Cks1 was shown to interact with both CDK1 (Draetta,1987) and CDK2 in higher eukaryotes (1BUH) (Bourne,1996; Zhang,1995). Similar to yeast and Xenopus, depletion of Cks1 in mouse embryonic fibroblasts causes cell cycle arrest in the G2 phase, and this effect was likely related to a decrease in Cyclin B1, Cyclin A, and CDK1 expression (Martinsson-Ahlzen,2008).
These results show that Cks1 regulates several steps of the cell cycle and plays a prominent role in cell cycle phase transitions. An important role of Cks1 in cell cycle regulation is to increase the specificity and efficiency of CDK-catalysed phosphorylation by providing an additional docking site for primed CDK substrates. Specific binding to Cks1 is mediated by the phospho-dependent Cks1-binding motif present in several CDK substrates. This motif forms a multipartite binding site with the CDK modification motif (MOD_CDK_1) and the cyclin-binding docking motif (DOC_CYCLIN_1). The crystal structure of the Cks1-CDK2 complex further shows that the catalytic domain of CDK2 and the motif-binding domain of Cks1 are located in spatial proximity, indicating that during binding the CDK modification site and the Cks1-binding motif on the substrate are located in spatial proximity (1BUH) (Bourne,1996). However, Cks1 might also provide a docking site for regulators of CDK activity such as the yeast Swe1 kinase (McGrath,2013). In addition, Cks1, in cooperation with the F box protein Skp2, also controls CDK activity by mediating the degradation of CDK inhibitors such as p27Kip1 through phospho-dependent recognition of a specific degron (DEG_SCF_SKP2-CKS1_1) in these inhibitors (Hao,2005).