DESCRIPTION (provided by applicant): The control of cell architecture involves coordination of diverse processes, and is closely coupled with mitotic regulation and cell fate determination. This control is fundamental to embryonic development and tissue function;its derangement is an important aspect of numerous human diseases. Essential structural systems and regulatory mechanisms involved in cell morphogenesis are broadly conserved, and critical understanding of human regulatory networks has derived from studies of related pathways in budding yeast. The yeast RAM network is a novel signaling pathway required for polarized growth and asymmetric transcription during exit from mitosis;it is highly conserved, but poorly understood. This project's goals are to determine how the RAM network functions in morphogenesis control and to define the mechanisms that link its activity to mitotic progress. Our efforts largely focus on Cbk1, an Ndr/LATS family protein kinase;these enzymes are conserved from Paramecium to humans. We have defined mechanisms important for control of Cbk1 and recently determined its phosphorylation consensus motif, which is distinctive and previously unknown for Ndr kinases. Using a combination of hypothesis-driven studies and genome-scale systematic genetic interaction analysis we will identify regulatory targets of the kinase that are relevant to cell morphogenesis. We will also determine how RAM network function is coordinated with mitosis. We will focus on defining how a critical regulatory modification triggers Cbk1's function during the M/G1 transition and following up on our preliminary evidence that the mitotic polo-like kinase Cdc5 directly regulates Cbk1 and the RAM network. PUBLIC HEALTH RELEVANCE: All organs are composed of cells that adopt shapes that are appropriate for the tissue. This requires exacting control of cell architecture;in numerous diseases, including cancer, this is deranged. This proposed research seeks to understand how a newly-discovered system for cell shape control works.
|Effective start/end date||8/1/10 → 7/31/12|
- National Institute of General Medical Sciences (3R01GM084223-03S1)