How specificity is maintained when distinct eukaryotic signal transduction systems share components is a central issue in cell biology that is highly relevant to human cancer. Our long-term objective is a detailed molecular understanding of this ubiquitous phenomenon. To address this question, we have exploited the powerful model system of the budding yeast S. cerevisiae. In this organism, eight proteins are shared between two MAP kinase cascades that signal two distinct developmental programs: 1) the mating pheromone response, and 2) the switch of filamentous growth. Pheromone signaling activates the mating pathway MAPK Fus3. However, due to the sharing of upstream kinases, a fraction of the filamentation pathway MAPK Kss2 is also activated. Our work has revealed that the effects of cross-talk are suppressed because Fus3 induces the phosphorylation and destruction of Tec1, the transcription factor that is activated inducing filamentation-specific transcription via Tec1. To further our understanding of signaling specificity, we will identify the determinants of Tec1 degradation kinetics during mating differentiation, test the hypothesis that there are rapid mechanisms by which Tec1 is inactivated prior to its bulk degradation, and determine how Tec1 is inactivated by the Hog1 MAPK to prevent cross-talk during salt-induced activation of the HOG pathway. Although signaling mechanisms are involved in numerous pathological processes, our studies relate in a particularly important way to human cancer. Tumor proliferation is caused in part by the inappropriate activation of growth-promoting signaling pathways, particularly the Erk MAP kinase pathway, because ras activity induces senescence in precancerous lesions but proliferation in frank malignancies, yet at understanding the principles that determine the specificity of MAP kinase signaling and therefore speak to this central question in oncogenesis.
|Bao, Marie Z; Shock, Teresa R; Madhani, Hiten D (2010) Multisite phosphorylation of the Saccharomyces cerevisiae filamentous growth regulator Tec1 is required for its recognition by the E3 ubiquitin ligase adaptor Cdc4 and its subsequent destruction in vivo. Eukaryot Cell 9:31-6|
|Shock, Teresa R; Thompson, James; Yates 3rd, John R et al. (2009) Hog1 mitogen-activated protein kinase (MAPK) interrupts signal transduction between the Kss1 MAPK and the Tec1 transcription factor to maintain pathway specificity. Eukaryot Cell 8:606-16|
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|Madhani, Hiten D (2006) Functional analysis of protein kinase networks in living cells: beyond ""knock-outs"" and ""knock-downs"". Methods 40:251-4|
|Schwartz, Monica A; Madhani, Hiten D (2006) Control of MAPK signaling specificity by a conserved residue in the MEK-binding domain of the yeast scaffold protein Ste5. Curr Genet 49:351-63|
|Bao, Marie Z; Schwartz, Monica A; Cantin, Greg T et al. (2004) Pheromone-dependent destruction of the Tec1 transcription factor is required for MAP kinase signaling specificity in yeast. Cell 119:991-1000|
|Schwartz, Monica A; Madhani, Hiten D (2004) Principles of MAP kinase signaling specificity in Saccharomyces cerevisiae. Annu Rev Genet 38:725-48|