Title: Cell-cycle Regulation of LAMMER-related Kinases

PI: Zhaohua Irene Tang

Funding Agency: NSF

Division: Molecular and Cellular Biosciences----Signal Transduction and Regulation

NSF Program: Gene Expression

Amount: $ 352,000

Dates: 04/2005 – 04/2008.  Originally for 3 years and extended to 04/2009. 

Abstract

The long-term objective of the project is to study important molecular targets for deciphering the regulatory mechanisms of cell life and death, and to gain new knowledge about how a cell functions as a basic unit of life.  Protein kinases are enzymes that catalyze the reactions to add a phosphate group to a protein, thereby regulating the function of the protein.  Protein kinases comprise one of the largest gene families in living organisms including mammals, and through reversible phosphorylation of substrates they mediate signal transduction pathways that control virtually every aspect of cell function and survival.  The goal of this project is to investigate the regulation of Schizosaccharomyces pombe fission yeast Dsk1 and Kic1 protein kinases during the cell cycle.  Dsk1 and Kic1 belong to a newly emerging class of dual-specificity protein kinases, the prototypes of which are featured with the “LAMMER” signature motif.  These LAMMER-related kinases are implicated in the regulation of cell growth, death, and differentiation during development including neurogenesis.  Although critical, the regulation of the LAMMER kinases in response to external signals and internal cues for cell survival and function remains unclear.  The project aims to build upon the earlier work on Dsk1 and Kic1 by the Principle Investigator and to gain a better understanding of their function in cell growth and proliferation.  This research is set forth with specific aims to test the hypothesis that Dsk1 and Kic1 are differentially phosphorylated, that the activities of Dsk1 and Kic1 are regulated by the differential phosphorylation during the cell cycle, and that their cellular localization changes in a cell cycle-dependent manner.  Since the counterparts of Dsk1 and Kic1 kinases in mammals play causal roles in cell growth and programmed cell death, in differentiation including neuronal stem cell induction, in hepatitis B virus infection, and in cellular sensitivity to anti-cancer drugs such as cisplatin, they are imperative targets for deciphering the principles that govern cell life and death.  Studies on fission yeast Dsk1 and Kic1 will fill the gap in the in vivo investigation of the kinase families and shed light on the biological roles of the kinases, which are fundamental to all living organisms.