Activation of CDK Cyclin complex

A number of potentially fatal human diseases like cancer involve cell cycle defects. Cell cycle control is regulated by an evolutionarily conserved family of serine/threonine protein kinases calledcyclin-dependent kinases (Cdks) and their regulatory subunits, the cyclins. Critical cell cycle events are both positively and negatively regulated by specific Cdks, whose activities oscillate throughout the cell cycle. Cdk activities are controlled by several different mechanisms, including binding of the positively activating cyclin subunits, inhibition by Cdk inhibitor proteins, phosphorylation by Cdk activating kinases (CAKs) or inhibitory kinases, and dephosphorylation by cell-cycle regulated phosphatases.

The founding members of the cyclinfamily, cyclins A and B, were first discovered as proteins that oscillated throughout the cell cycle, peaking in late G2 and M phase. These proteins were later shown to be required to activate Cdk1, (also known as Cdc2), which is required for entry into M phase in most eukaryotes. At the N terminus of these mitotic cyclins, there is a 9-amino acid destruction motif (RXALG[D/N/E/V]IXN) (D box), which targets the protein for ubiquitin-dependent degradation by the 26S proteasome during mitosis. Ubiquitination is mediated by an E3 ubiquitin ligase known as anaphase promoting complex (APC), which has several key targets during mitosis. For example, securin, the inhibitor of separase, needs to be degraded at the onset of anaphase to promote sister chromatid separation.