El Dika M , Dudka D , Kloc M , Kubiak JZ .

613 Wojskowy Instytut Medyczny

             embryo development
             cyclin B1-CDK1 complex
             cyclin B2-CDK1 complex

	Graphical Abstract
	Figure 1. A regulatory network between CDK1, Bora-Aurora A, Plk1, Gw1-PP2A, and CDC25 upon mitotic entry. Before mitosis, CDK1 is activated when cyclins A and B reach a threshold concentration. The mitotic cyclin-associated CDK1 phosphorylates the Bora protein, activating Plk1. Additionally, Bora and Aurora A kinase interact to stimulate Plk1 activity. Parallel to this, CDK1 stimulates Gw1 activity, which inhibits PP2A (Protein Phosphatase 2A) and promotes the activation of CDC25. This activates CDK1’s amplification loop, which blocks PP2A via Gw1 and effectively activates Plk1 by Bora-Aurora A. As a result, the regulatory network between all these proteins controls the time when CDK1 amplification becomes fully activated, and how the mitosis progresses after that.
	Figure 2. A model of the role of CDC6 in the control of the M-phase entry. The first, potentially active CDK1 molecules start to appear after the cyclin A level reaches a predetermined threshold, but they are actively inhibited by CDC6/Xic1. The first active CDK1/cyclin A molecules appear when they escape from CDC6-dependent inhibition, while CDK1/cyclin B complexes are inhibited by both CDC6/Xic1- and Wee1/Myt1-dependent mechanisms. This is the step of the initial activation of CDK1. In parallel, both cyclin A and B levels continue to increase with time and keep associating with CDK1. The active CDK1/cyclin A and CDK1/cyclin B complexes become more abundant, and they, or only CDK1/cyclin B, become able to phosphorylate its substrates—Bora and Gw1. Due to this activation of Plk1 via these two distinct pathways, the procedure is highly effective, which in turn promotes CDC25 activity acting as the CDK1 amplification loop.

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