In budding yeast, the final cell cycle transition, exit from mitosis, is governed by the Mitotic Exit Network (MEN), a GTPase signaling cascade. The homologous pathway in mammals is known as the Hippo/Lats pathway, a major regulator of organ size and organismal growth in animals. Our recent work led to the exciting finding that multiple signals control the activity of the Mitotic Exit Network and that MEN regulation does not solely occur through the GTPase switch but that the GTPase effector kinase also receives and integrates regulatory signals.
In Specific Aim 1 we will determine how a spatial signal, spindle position controls MEN activity and hence exit from mitosis.
In Specific Aim 2 we will investigate how a temporal signal, anaphase entry, ensures that the MEN is only active during the final stages of the cell cycle. Finally, in Specific Aim 3 we will investigate how other GTPase signaling components function as signal recipients. We will study how the GTPase effector kinase integrates signals from the MEN GTPase and the Polo kinase Cdc5. The experiments proposed here will significantly contribute to our understanding of cell cycle control and how the order of events of the cell cycle are established, a cell cycle feature often lost during abnormal development and diseases such as cancer. They will uncover the molecular mechanisms that ensure that exit from mitosis only occurs after chromosomes have been segregated and each daughter cell has received a complete complement of the genome. Our studies will also have a significant impact on the GTPase signaling field. Our work on a GTPase pathway that governs exit from mitosis led to the realization that GTPase signaling pathways are not only regulated at the level of the GTPase switch but at subsequent signaling step. Understanding how GTPase effector kinases serve as signal recipients is a still poorly understood aspect of GTPase signaling. GTPase signaling pathways are central regulators of cell growth and proliferation and development. Understanding GTPase signaling at the molecular level is thus vital for understanding the principles underlying normal cell growth proliferation and abnormal development and disease states.
Cell cycle control is central to the growth and development of organisms. Defects in the process lead to cell death, growth and developmental defects and diseases such as cancer. We study how the final cell cycle transition, exit from mitosis, is integrated with other cell cycle events, specifically chromosome segregation and nuclear position. Both events control a GTPase signaling pathway known as the Mitotic Exit Network, which triggers exit from mitosis in yeast. The homologous pathway in mammals is known as the Hippo/Lats pathway, a major regulator of organ size and organismal growth in animals. This proposal describes experiments to determine how the Mitotic Exit Network senses chromosome segregation and nuclear position and integrates these events. Our work leading up to this proposal led to the exiting discoveries that (1) the Mitotic Exit Network GTPase responds to multiple signals and (2) that the Mitotic Exit Network is not only regulated at the level of the GTPase switch but at subsequent signaling steps. The GTPase effector kinase also response to cell cycle events and contributes to restricting Mitotic Exit Network activity to exit from mitosis The experiments proposed here will contribute to our understanding of these still poorly understood aspects of GTPase signaling not only in the Hippo pathway but GTPase signaling pathways in general. They may also well pave the way towards the identification of new ways in which GTPase signaling is mis-regulated in disease states causing abnormal growth and development.
|Santaguida, Stefano; Richardson, Amelia; Iyer, Divya Ramalingam et al. (2017) Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System. Dev Cell 41:638-651.e5|
|Falk, Jill Elaine; Tsuchiya, Dai; Verdaasdonk, Jolien et al. (2016) Spatial signals link exit from mitosis to spindle position. Elife 5:|
|Falk, Jill E; Campbell, Ian W; Joyce, Kelsey et al. (2016) LTE1 promotes exit from mitosis by multiple mechanisms. Mol Biol Cell 27:3991-4001|