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FIGURE 7:. (A) Cdk substrate phosphorylation regulatory network. The phosphorylation of mitotic substrates (enzymes and structural proteins) by Cdk1/cyclin B complex underlies mitotic entry. Cdk1/cyclin B is antagonized by phosphatases PP1 and PP2A that dephosphorylate mitotic substrates. Wee1 kinase and Cdc25 phosphatases regulate Cdk1 activity: Wee1 inhibits Cdk1 (green inhibitory line) and Cdc25 activates it (blue arrow). Wee1 and Cdc25 are themselves Cdk substrates. Cdk1 phosphorylates and inhibits Wee1, preventing Wee1 from inactivating Cdk1. Also, Cdk1 phosphorylates and activates its activator Cdc25. Active Cdk also inhibits antagonists PP1 and PP2A by at least two known mechanisms. First, Cdk1 can inhibit PP1 directly by phosphorylating T320 residue on a catalytic subunit of the phosphatase (black inhibitory line). Second, Cdk1 phosphorylates and activates the Greatwall/MastL kinase, which inhibits PP2A and possibly PP1 by yet unidentified mechanisms (red inhibitory line). Therefore as Cdk activation is fueled by positive feedback, it also promotes the inactivation of its antagonists, ensuring the stability of substrate phosphorylation. (B) Failure to activate Cdk rapidly results in mitotic collapse after nuclear envelope breakdown. The feedback-mediated activation of the Cdk1/Cyclin B complex may be required to prevent the dilution of the kinase activity throughout the cytoplasm when the nuclear envelope becomes permeable. Cdk1 activity appears to spike around the time of the nuclear envelope disassembly, when the activated Cdk/cyclin B complex spreads through the cytoplasm. In the absence of the positive feedback, active Cdk1 would be diluted in the cytoplasm when the nuclear envelope becomes permeable. In the absence of positive feedback mechanisms, the concentration of the active kinase per unit of cytosol may fall below the level that is needed to efficiently counteract Cdk-opposing phosphatases, which leads to the mitotic collapse. Image published in: Potapova TA et al. (2011) © 2011 Potapova et al. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license Larger Image Printer Friendly View

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