MOD_CDK_SPxxK_3

Protein phosphorylation is a key regulatory mechanism for cell cycle regulation in eukaryotes. Progression of cells through the cell cycle is tightly regulated by cyclin-CDK dimeric kinase complexes where CDK is the catalytic kinase subunit and cyclin is the activating subunit. In higher organisms different CDKs associate with one or more different cyclins at specific phase of cell cycle. Of the 20 CDKs identified, CDK1-11 are the best characterized. CDK1, 2, 3, 4 and 6 are key players with major regulatory roles in core cell cycle at different phases like G1/S (CDK3, 4, 6), S (CDK2) and G2/M (CDK1). CDK5 functions primarily in neuronal development and CDK 7,8,9,10,11 function mainly as transcriptional regulators. Most CDKs and their associated cyclins have tightly controlled cell phase-specific expression. Cyclin D functions during G1/S, cyclin E at S phase and cyclin A/B classes at G2/M (Malumbres,2009).
CDKs are proline-directed serine/threonine-protein kinases with classically a preference for the [ST]P.KR] sequence as a consequence of the presence of a hydrophobic pocket near the catalytic site that accommodates the proline (position +1) (Brown,2001) and negative charge to bind the Lys/Arg. However, the requirement for the basic residue in the +3 position is not strictly maintained in all CDKs. Some display a preference for a short [ST]P[RK] consensus site (Lees,1992) while others show preference for a long CDK phosphorylation site ([ST]P..[KR]) (Hodeify,2011). There are also even longer SP…[KR] reports (not yet annotated in ELM) (Esashi,2005). There are in addition some reports of CDK phosphorylation sites which require only an SP motif and others even suggesting non-SP sites (25604483). CDKs can be specific to particular substrates but also at the same time they may have overlapping substrate specificity: Partly this may be done to differences in spatio-temporal regulation. Also different CDKs can phosphorylate the same substrate on different sites to effect different substrate functions. So the identification of substrates of specific CDK-Cyclin complexes is important as both the substrate specificity and availability are necessary to ensure that the right cellular events are understood to occur in the right order.
Since CDKs have been found deregulated in many human cancers, they are considered as interesting therapeutics targets in cancer. For example the inhibitor of CDK4/6 has been tested in Phase 3 clinical trials e.g. PALOMA-3 (26947331).