Figure 2. Feedback loops that regulate cyclin B–Cdk1 activity. (A) The inner feedbacks. Myt1 and Wee1 kinases phosphorylate Cdk1 on T14 and Y15, thereby inhibiting cyclin B–Cdk1 activity. The T14 and Y15 phosphorylations can be antagonized by Cdc25A, -B, and -C. Once activated, cyclin B–Cdk1 activity inhibits Wee1 and Myt1, and activates the Cdc25 phosphatases. Thus, by the inner feedback loops, cyclin B–Cdk1 inhibits its inhibitors and activates its activators. (B) Direct Plk1-dependent feedback. Cyclin B–Cdk1 phosphorylation of many targets, including Wee1, Myt1, and Cdc25C, creates a docking site for Plk1. Binding of Plk1 both guides Plk1 to its substrate and stimulates Plk1 activity by releasing its inhibitory polo-box domains. In this way, cyclin B–Cdk1–mediated phosphorylation can trigger a second round of Plk1-mediated phosphorylation of a target protein. (C) Feedback through Bora-Aurora-Plk1. Cyclin B–Cdk1–mediated phosphorylation of Bora increases Bora binding to Plk1. Bora can also associate with Aurora A, and is required for efficient Aurora A–mediated activation of Plk1. By regulating Bora phosphorylation, cyclin B–Cdk1 can thereby activate Plk1. Plk1 in turn activates cyclin B–Cdk1 at different levels (Fig. 2, B, D, and E). Aurora A can also stimulate cyclin B–Cdk1 activation through activation of Cdc25B and regulation of centrosome maturation (Fig. 2 D). Although Aurora A activity is regulated by Cdk, it is currently unclear if these processes depend on cyclin B–Cdk1–mediated phosphorylation of Bora. (D) Feedback through centrosome maturation. The local concentration of cyclin B–Cdk1, an important regulatory step for cyclin B–Cdk1 activation, is enhanced by targeting to the maturating centrosome in late G2 phase. Moreover, many additional proteins in the mitotic entry network are targeted to centrosomes, thereby creating high local concentrations of cyclin B–Cdk1 activators. Both Aurora A and Plk1 activities are required for centrosome maturation and stimulate cyclin B accumulation on centrosomes. (E) Feedback through transcription. Plk1 directly activates the transcription factor FoxM1. FoxM1 stimulates the expression of multiple proteins in the mitotic entry network, including cyclin B. Thus, cyclin B–Cdk1–mediated activation of Plk1 through Bora/Aurora A increases the production of several cyclin B–Cdk1 activators, thereby further stimulating cyclin B–Cdk1 activation.
Figure 2.

Feedback loops that regulate cyclin B–Cdk1 activity. (A) The inner feedbacks. Myt1 and Wee1 kinases phosphorylate Cdk1 on T14 and Y15, thereby inhibiting cyclin B–Cdk1 activity. The T14 and Y15 phosphorylations can be antagonized by Cdc25A, -B, and -C. Once activated, cyclin B–Cdk1 activity inhibits Wee1 and Myt1, and activates the Cdc25 phosphatases. Thus, by the inner feedback loops, cyclin B–Cdk1 inhibits its inhibitors and activates its activators. (B) Direct Plk1-dependent feedback. Cyclin B–Cdk1 phosphorylation of many targets, including Wee1, Myt1, and Cdc25C, creates a docking site for Plk1. Binding of Plk1 both guides Plk1 to its substrate and stimulates Plk1 activity by releasing its inhibitory polo-box domains. In this way, cyclin B–Cdk1–mediated phosphorylation can trigger a second round of Plk1-mediated phosphorylation of a target protein. (C) Feedback through Bora-Aurora-Plk1. Cyclin B–Cdk1–mediated phosphorylation of Bora increases Bora binding to Plk1. Bora can also associate with Aurora A, and is required for efficient Aurora A–mediated activation of Plk1. By regulating Bora phosphorylation, cyclin B–Cdk1 can thereby activate Plk1. Plk1 in turn activates cyclin B–Cdk1 at different levels (Fig. 2, B, D, and E). Aurora A can also stimulate cyclin B–Cdk1 activation through activation of Cdc25B and regulation of centrosome maturation (Fig. 2 D). Although Aurora A activity is regulated by Cdk, it is currently unclear if these processes depend on cyclin B–Cdk1–mediated phosphorylation of Bora. (D) Feedback through centrosome maturation. The local concentration of cyclin B–Cdk1, an important regulatory step for cyclin B–Cdk1 activation, is enhanced by targeting to the maturating centrosome in late G2 phase. Moreover, many additional proteins in the mitotic entry network are targeted to centrosomes, thereby creating high local concentrations of cyclin B–Cdk1 activators. Both Aurora A and Plk1 activities are required for centrosome maturation and stimulate cyclin B accumulation on centrosomes. (E) Feedback through transcription. Plk1 directly activates the transcription factor FoxM1. FoxM1 stimulates the expression of multiple proteins in the mitotic entry network, including cyclin B. Thus, cyclin B–Cdk1–mediated activation of Plk1 through Bora/Aurora A increases the production of several cyclin B–Cdk1 activators, thereby further stimulating cyclin B–Cdk1 activation.

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