Our current work is focused on the following questions:
How do cells measure and limit their growth?
In all cells, key cell cycle transitions occur only when sufficient growth has occurred, which ensures that cells maintain a constant size. Thus, cells must convert growth into a proportional signal that triggers cell cycle progression when it reaches a threshold. The mechanisms by which cell growth is measured have remained deeply mysterious. Our recent work suggests that vesicles that drive plasma membrane growth deliver signaling lipids to the growing membrane, which bind and activate conserved signaling proteins to generate a signal that is proportional to the extent of growth. We further discovered signaling networks that could read the growth-dependent signal and trigger cell cycle progression when it reaches a threshold. Growth-dependent signaling suggests a simple and broadly applicable solution to control of cell growth and size. We are currently testing key hypotheses arising from these discoveries, while also carrying out mechanistic analysis to define the signaling networks that control cell growth and size.
What are the signals that control cell growth and size?
Observations reaching back over 60 years suggest that control of cell growth and cell size are closely linked. For example, growth rate is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. These relationships appear to hold across all orders of life, which suggest that they reflect fundamental principles, yet the underlying mechanisms have remained elusive. We discovered that signals arising from a conserved TORC2 signaling network enforce proportional relationships between nutrient availability, cell growth, and cell size. Our work suggests a model in which TORC2-dependent signals that set growth rate also set the threshold amount of growth required for cell cycle progression, which would provide a simple mechanistic explanation for proportional relationships between cell size and growth rate. We are currently searching for the upstream signals that control the TORC2 network as well as the signaling outputs of the network that influence cell growth and size.
How is control of cell growth and size disrupted in cancer cells?
Severe defects in control of cell growth and size are a nearly universal feature of cancer cells, yet little is known about the underlying molecular defects. We have recently initiated new projects aimed at translating our discoveries in yeast into an understanding of how cell growth and size are controlled in vertebrate cells. Our goal is to define conserved mechanisms that control cell growth and size, and how these mechanisms go awry in cancer cells.