The reversible phosphorylation of proteins is a major regulatory mechanism that controls cell cycle progression and development in all eukaryotic organisms. Meiosis and spore formation in yeast (sporulation) provides an outstanding model system to study protein kinase signaling pathways. Similar to developmental programs in higher eukaryotes, induction of sporulation is controlled by a combination of cell-type and environmental signals. Once initiated, a transcriptional cascade of cell-type specific genes ultimately leads to a cell that is genetically and biochemically distinct from the starting cell. A protein kinase network has been identified that controls multiple steps in meiotic development. A central component of this network is the activating kinase Cak1. During sporulation Cak1 is required for activation of the MAP kinase homolog Smk1, the CDK-like kinase Ime2, and the CDK Cdc28. The CAK1, IME2 and SMK1 genes are tightly regulated by the transcriptional cascade of sporulation. This network controls meiotic progression at multiple self-reinforcing steps through DNA-binding and chromatin-modifying regulatory proteins. The goal of this proposal is to identify new components of the Cak1/Ime2/Smk1 protein kinase network, to elucidate molecular mechanisms that control its activities, and to identify targets that couple signaling to meiotic progression.
The specific aims of the proposal are: 1- Elucidate how Cak1 activates the Smk1 MAP kinase. 2- Elucidate how Ime2 is regulated by phosphorylation 3- Elucidate molecular mechanisms that regulate mid-late sporulation-specific gene expression, and 4- Identify negative regulators of the Smk1 pathway using genetic suppression approaches. These studies will provide mechanistic insights into how protein kinase networks control developmental programs in general and meiotic development in particular.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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Anderson, Richard A
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Thomas Jefferson University
Schools of Medicine
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Shin, Marcus E; Skokotas, Aikaterini; Winter, Edward (2010) The Cdk1 and Ime2 protein kinases trigger exit from meiotic prophase in Saccharomyces cerevisiae by inhibiting the Sum1 transcriptional repressor. Mol Cell Biol 30:2996-3003
Ahmed, Noreen T; Bungard, David; Shin, Marcus E et al. (2009) The Ime2 protein kinase enhances the disassociation of the Sum1 repressor from middle meiotic promoters. Mol Cell Biol 29:4352-62
McDonald, Christine M; Wagner, Marisa; Dunham, Maitreya J et al. (2009) The Ras/cAMP pathway and the CDK-like kinase Ime2 regulate the MAPK Smk1 and spore morphogenesis in Saccharomyces cerevisiae. Genetics 181:511-23
Moore, Michael; Shin, Marcus E; Bruning, Adrian et al. (2007) Arg-Pro-X-Ser/Thr is a consensus phosphoacceptor sequence for the meiosis-specific Ime2 protein kinase in Saccharomyces cerevisiae. Biochemistry 46:271-8
Schindler, Karen; Winter, Edward (2006) Phosphorylation of Ime2 regulates meiotic progression in Saccharomyces cerevisiae. J Biol Chem 281:18307-16
McDonald, Christine M; Cooper, Katrina F; Winter, Edward (2005) The Ama1-directed anaphase-promoting complex regulates the Smk1 mitogen-activated protein kinase during meiosis in yeast. Genetics 171:901-11
Bungard, David; Reed, Michelle; Winter, Edward (2004) RSC1 and RSC2 are required for expression of mid-late sporulation-specific genes in Saccharomyces cerevisiae. Eukaryot Cell 3:910-8
Schaber, Michael; Lindgren, Anne; Schindler, Karen et al. (2002) CAK1 promotes meiosis and spore formation in Saccharomyces cerevisiae in a CDC28-independent fashion. Mol Cell Biol 22:57-68