Control of cell growth and size: A fundamental unsolved problem
Cell growth during the cell cycle must be precisely controlled to ensure that cell division yields two viable cells of a defined size. The mechanisms that control cell growth and size must be as ancient and conserved as the cell cycle, since they would have been necessary for survival of the earliest eukaryotic cells. The goal of our work is to discover conserved universal mechanisms that control cell growth and size. These mechanisms are likely to be highly relevant to cancer because severe defects in cell size are a nearly universal feature of cancer cells.
Cell size checkpoints play a critical role in cell size control
Cell size checkpoints ensure that key cell cycle transitions are initiated only when sufficient growth has occurred. Theoretical considerations suggest that cell size checkpoints must translate a parameter related to growth into a proportional checkpoint signal that can be read to determine when sufficient growth has occurred. They must also read the proportional checkpoint signal and trigger a cell cycle transition when it reaches a threshold. Our work is aimed at discovering the molecular mechanisms underlying these key mechanistic features of cell size checkpoints.
Growth-dependent signaling could explain how cell size checkpoints measure growth
We recently discovered a checkpoint that links mitotic entry to membrane growth in budding yeast. Our analysis of the checkpoint led us to hypothesize that vesicles arriving at a site of membrane growth generate a checkpoint signal that is proportional to the extent of growth, and that downstream components read the strength of this signal to determine when sufficient growth has occurred. This growth-dependent signaling hypothesis suggests a simple and broadly relevant solution to two fundamental biological questions: 1) How is cell size controlled? and 2) How is membrane growth integrated with the cell cycle? Growth-dependent signaling could control both size and shape by determining the extent of growth at specific sites. It also suggests a robust mechanism for size control that is readily adaptable to cells of diverse size and shape. We are using proteomics, biochemistry, genetics and in vivo imaging to explore the mechanisms that link cell cycle progression to membrane growth.
Discovery of a master regulator of cell size
Protein phosphatase 2A associated with the Rts1 regulatory subunit (PP2ARts1) plays a central role in size control in budding yeast. Cells that lack PP2ARts1 fail to modulate their size in response to nutrients, which indicates that PP2ARts1 plays a role in the enigmatic mechanisms that set cell size. To identify targets of PP2ARts1, we used quantitative proteome-wide mass spectrometry, which revealed that PP2ARts1 is a master regulator of multiple cell size checkpoint pathways. Thus, multiple seemingly independent cell size checkpoints may be linked to a common mechanism that sets cell size. Our proteome-wide analysis of proteins controlled by PP2ARts1 led to the discovery of numerous candidate targets, key phosphorylation sites, and entire signaling pathways controlled by PP2ARts1. The data have thus proven to be a rich trove of information that we are using as a roadmap to discover mechanisms of cell size control.