A wide variety of cell types delay cell cycle transitions until they reach a critical size threshold, but the mechanisms that measure size and transmit this information to the core cell cycle machinery are largely unknown. The protein kinase Cdr2 connects cell size measurement with mitotic entry in fission yeast, and is part of a conserved family of protein kinases that down- regulate the mitotic inhibitor Wee1 in yeast and human cells. To understand the function of Cdr2 in cell size checkpoints, it is important to define the upstream signals that control Cdr2 activity and localization. We are using combined genetic, biochemical, and microscopy approaches to identify Cdr2 regulatory circuits and to determine how their input-output behaviors depend on cell size. Our initial work implicates three molecular "input" signals to Cdr2: the polarity kinase Pom1, the methyltransferase Skb1, and phosphorylation in the Cdr2 activation loop by an unknown kinase.
The specific aims of the project are to: (1) define how phosphorylation by Pom1 inhibits Cdr2 in cells, (2) identify the Skb1 signaling pathway that controls Cdr2, and (3) determine the role of Cdr2 activation loop phosphorylation in the mitotic size control system. Successful completion of these goals will advance scientific knowledge by identifying the mechanisms that coordinate cell growth and division through the activity of core cell cycle proteins. Moreover, the sizing mechanisms that we uncover will provide insights for how size controls the activity of other biological systems.
Defects in the mitotic entry control system can lead to genomic instability, a hallmark of cancer. We will use the model organism fission yeast to define of the upstream signals that govern this cell cycle transition. These findings will be important to understand the cellular mechanisms that prevent untimely and inappropriate cell divisions, which contribute to human diseases such as cancer.
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