Doug Kellogg

Doug Kellogg Professor of MCD Biology
B.A., University of Wisconsin, Madison
Ph.D., University of California, San Francisco
Postdoctorate, University of California, San Francisco

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CONTROL OF CELL GROWTH AND SIZE

Control of cell size and shape:  A fundamental unsolved problem

Cells must maintain a specific size and shape to survive and carry out their functions.  The mechanisms that control cell size and shape 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, size and shape.

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.  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.  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 work

We recently discovered a new checkpoint mechanism that links mitotic entry to membrane growth in budding yeast.  Our discoveries led to a novel hypothesis:  we propose 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.  We refer to this as the growth-dependent signaling hypothesis.

Growth-dependent signaling 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 would also provide 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 conserved Rts1 subunit (PP2ARts1) plays key roles 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 fundamental 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 coordinately controls cell growth and 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.of the mechanisms used by Cdk1 to initiate and maintain cell growth during G1.

Please follow this link to find the lab's publications in the National Library of Medicine's PubMed database.