Research Interests


	Wild type cells	Cell Cycle mutant cells

Cells show extraordinary diversity in size and shape. Generation of diverse sizes and shapes requires regulation of the amount and location of growth, as well as coordination of cell growth with cell division. The mechanisms by which cells regulate cell growth and size are poorly understood and represent one of the most important and fundamental unsolved problems in cell biology. The goal of our work is to elucidate these mechanisms.

Coordination of cell growth and cell division

Entry into mitosis is initiated by synthesis of mitotic cyclins, which bind and activate cyclin-dependent kinase 1 (Cdk1). Activation of Cdk1 at the G2/M transition is tightly regulated by the Wee1 kinase and the Cdc25 phosphatase. Wee1 phosphorylates and inhibits Cdk1, thereby delaying entry into mitosis, while Cdc25 removes the inhibitory phosphorylation and promotes entry into mitosis. Both Wee1 and Cdc25 have been highly conserved, suggesting that similar mechanisms control entry into mitosis in all eukaryotic cells.

In fission yeast and budding yeast, Wee1 is thought to delay entry into mitosis until a critical cell size has been reached. An understanding of the mechanisms that regulate Wee1 and Cdc25 will therefore provide important insight to the mechanisms that link cell growth to cell division. Our recent work suggests that these proteins are regulated by an unusual and highly dynamic signaling network. It is likely that the network behaves as a dynamic sensor that can continuously assess growth status and then trigger entry into mitosis when sufficient growth has occurred.

Mechanisms that initiate cell growth

In budding yeast, the G1 cyclins bind and activate Cdk1 to initiate new cell growth in G1. It is thought that the Cdk1 initiates new cell growth by activating the Cdc42 GTPase; however, the underlying mechanisms and the identity of the direct targets of Cdk1 that initiate growth have remained elusive. We have found that several proteins associated with Cdc42 are direct and specific targets of Cdk1 associated with G1 cyclins, thus providing a link between Cdk1 activity and proteins required for cell growth. We have also more carefully characterized the role of Cdk1 in controlling cell growth. Previous work suggested that Cdk1 is only required for initiation of cell growth; however, we have found that Cdk1 is required continuously for cell growth. Our long term goal is a detailed understanding of the mechanisms used by Cdk1 to initiate and maintain cell growth during G1.