The MAP kinases are components of an evolutionarily ancient signal transduction system. Other components include Ras, Raf-1, MEK kinase, Mos, and MEK, which lie upstream from MAP kinase, and Rsk, which lies downstream. MAP kinases relay signals from the membrane to the nucleus in a wide variety of biological contexts, including mitogenesis in tissue culture cells, the G2-M transition in Xenopus oocytes, and vulval induction in C. elegans. The work we propose here builds upon two recent observations. The first is that p42 MAP kinase and Rsk form a heterodimeric complex when the two kinases are inactive, and dissociate when active, which suggests that Rsk plays a particularly central role in MAP kinase signaling. The second is that MPF can bring about p42 MAP kinase activation, even in the absence of protein synthesis. We plan to carry out biochemical and genetic analyses of the interaction between MAP kinase and Rsk, and biochemical analysis of the interaction between MAP kinase and MPF: (1) Biochemical analysis of MAP kinase and Rsk. We plan to reconstitute the p42 MAP kinase/Rsk complex in vitro, and to determine how phosphorylation of each protein affects the stability of the complex. We shall carry out structure/function analyses to determine what regions within the two proteins are essential for complex formation. We shall search for mutants of the two proteins that are incapable of forming complexes, or incapable of dissociating once in a complex, and use the mutants to evaluate the significance of complex formation in vivo. (2) Genetic analysis of Rsk function in C. elegans. We plan to identify a C. elegans homolog of rsk, and to obtain or produce rsk mutants. We shall determine how the rsk mutants interact genetically with MAP kinase mutants in the worm, and how they interact biochemically with MAP kinase mutants when expressed in Xenopus oocytes. (3) Biochemical analysis of the pathway from MPF to MAP kinase. We shall determine how MPF brings about p42 MAP kinase activation by tracing the p42 MAP kinase pathway upstream. We shall investigate whether the p42 MAP kinase phosphatase is activated and inactivated in a cell cycle specific fashion. Our overall aim is to elucidate the regulation and role of p42 MAP kinase and Rsk in cell signaling.
| Kamenz, Julia; Ferrell Jr, James E (2017) The Temporal Ordering of Cell-Cycle Phosphorylation. Mol Cell 65:371-373 |
| Ha, Sang Hoon; Kim, Sun Young; Ferrell Jr, James E (2016) The Prozone Effect Accounts for the Paradoxical Function of the Cdk-Binding Protein Suc1/Cks. Cell Rep 16:2047 |
| Ferrell Jr, James E (2016) Perfect and Near-Perfect Adaptation in Cell Signaling. Cell Syst 2:62-7 |
| Ha, Sang Hoon; Kim, Sun Young; Ferrell Jr, James E (2016) The Prozone Effect Accounts for the Paradoxical Function of the Cdk-Binding Protein Suc1/Cks. Cell Rep 14:1408-1421 |
| Ha, S H; Ferrell Jr, J E (2016) Thresholds and ultrasensitivity from negative cooperativity. Science 352:990-3 |
| Gelens, Lendert; Huang, Kerwyn Casey; Ferrell Jr, James E (2015) How Does the Xenopus laevis Embryonic Cell Cycle Avoid Spatial Chaos? Cell Rep 12:892-900 |
| Ferrell Jr, James E; Ha, Sang Hoon (2014) Ultrasensitivity part I: Michaelian responses and zero-order ultrasensitivity. Trends Biochem Sci 39:496-503 |
| Gelens, Lendert; Anderson, Graham A; Ferrell Jr, James E (2014) Spatial trigger waves: positive feedback gets you a long way. Mol Biol Cell 25:3486-93 |
| Tsai, Tony Y-C; Theriot, Julie A; Ferrell Jr, James E (2014) Changes in oscillatory dynamics in the cell cycle of early Xenopus laevis embryos. PLoS Biol 12:e1001788 |
| Ferrell Jr, James E; Ha, Sang Hoon (2014) Ultrasensitivity part III: cascades, bistable switches, and oscillators. Trends Biochem Sci 39:612-8 |
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