The mechanisms that control cell size are largely unknown and represent a fundamental unsolved problem in biology. The size of proliferating cells is controlled by cell size checkpoints, which ensure that key cell cycle transitions are initiated only when sufficient growth has occurred. Despite their name, it is uncertain whether cell size checkpoints monitor a parameter linked to cell size, such as volume or surface area, or whether they monitor parameters linked to growth or biosynthetic capacity. The signals that link the cell cycle to cell size have remained deeply mysterious. We discovered that protein phosphatase 2A associated with the Rts1 subunit (PP2ARts1) is required for cell size control in budding yeast. Importantly, cells that lack PP2ARts1 fail to modulate their size in response to nutrients, which suggests that PP2ARts1 functions in the enigmatic mechanisms that set cell size. We used quantitative proteome-wide mass spectrometry to discover targets of PP2ARts1, which revealed that PP2ARts1 is a master regulator of multiple cell size checkpoint pathways. This important discovery suggests that multiple seemingly independent cell size checkpoints may be linked to a common mechanism that measures cell growth. We further found that PP2ARts1 itself is controlled by phosphoinositide-dependent kinase 1 (PDK1), which plays conserved roles in control of cell growth and size. Together, our recent discoveries have led us to hypothesize that common signals, working through PDK1 and PP2ARts1, coordinately control cell growth and size. We further hypothesize that PP2ARts1 works in a mechanism that translates growth into a proportional checkpoint signal that can be read to determine when sufficient growth has occurred. The proposed Aims use a combination of genetics, biochemistry, proteomics and imaging to test these hypotheses, while also laying the groundwork for new breakthroughs in cell size control.
Severe defects in cell size and shape are a nearly universal feature of cancer cells and have long been a basis of cancer pathology in the clinic. These defects may define a difference from normal cells that could be exploited to selectively kill cancer cells. To explore this novel idea, we need a better understanding of the mechanisms that control growth and size and how they go wrong in cancer cells.
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