A Mechanism for Cell-Cycle Regulation of MAP Kinase Signaling in a Yeast Differentiation Pathway

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell (Impact Factor: 32.24). 03/2007; 128(3):519-31. DOI: 10.1016/j.cell.2006.12.032
Source: PubMed


Yeast cells arrest in the G1 phase of the cell cycle upon exposure to mating pheromones. As cells commit to a new cycle, G1 CDK activity (Cln/CDK) inhibits signaling through the mating MAPK cascade. Here we show that the target of this inhibition is Ste5, the MAPK cascade scaffold protein. Cln/CDK disrupts Ste5 membrane localization by phosphorylating a cluster of sites that flank a small, basic, membrane-binding motif in Ste5. Effective inhibition of Ste5 signaling requires multiple phosphorylation sites and a substantial accumulation of negative charge, which suggests that Ste5 acts as a sensor for high G1 CDK activity. Thus, Ste5 is an integration point for both external and internal signals. When Ste5 cannot be phosphorylated, pheromone triggers an aberrant arrest of cells outside G1 either in the presence or absence of the CDK-inhibitor protein Far1. These findings define a mechanism and physiological benefit of restricting antiproliferative signaling to G1.

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    • "Cell 160, 1182–1195, March 12, 2015 ª2015 Elsevier Inc. 1187 MAPK pathway post-Start. Thus, while it is clear that cell-cycle progression inhibits pheromone signaling (Garrenton et al., 2009; Strickfaden et al., 2007; Torres et al., 2011), this inhibition is not complete at intermediate pheromone concentrations . Our data thus shows that intergenerational memory is composed of Far1 accumulated from the entire previous cell division cycle. "
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    ABSTRACT: Cells make accurate decisions in the face of molecular noise and environmental fluctuations by relying not only on present pathway activity, but also on their memory of past signaling dynamics. Once a decision is made, cellular transitions are often rapid and switch-like due to positive feedback loops in the regulatory network. While positive feedback loops are good at promoting switch-like transitions, they are not expected to retain information to inform subsequent decisions. However, this expectation is based on our current understanding of network motifs that accounts for temporal, but not spatial, dynamics. Here, we show how spatial organization of the feedback-driven yeast G1/S switch enables the transmission of memory of past pheromone exposure across this transition. We expect this to be one of many examples where the exquisite spatial organization of the eukaryotic cell enables previously well-characterized network motifs to perform new and unexpected signal processing functions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 03/2015; 160(6):1182-1195. DOI:10.1016/j.cell.2015.02.032 · 32.24 Impact Factor
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    • "Even if the optimal trait value is the same in all species, if the number of phosphorylation sites (loci) that contribute to the trait is large, a minimal level of conservation will be observed for the actual phosphorylation sites. For example, CDK-mediated inhibition of Ste5 membrane localization is mediated by 8 phosphorylation sites in S. cerevisiae (Figure 1; Serber and Ferrell, 2007; Strickfaden et al., 2007). The strength of the inhibition is proportional to the net charge of the Ste5 PM domain after phosphorylation by CDKs. "
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    ABSTRACT: Most proteins are regulated by posttranslational modifications and changes in these modifications contribute to evolutionary changes as well as to human diseases. Phosphorylation of serines, threonines, and tyrosines are the most common modifications identified to date in eukaryotic proteomes. While the mode of action and the function of most phosphorylation sites remain unknown, functional studies have shown that phosphorylation affects protein stability, localization and ability to interact. Two broad modes of action have been described for protein phosphorylation. The first mode corresponds to the canonical and qualitative view whereby single phosphorylation sites act as molecular switches that either turn on or off specific protein functions through direct or allosteric effects. The second mode is more akin to a rheostat than a switch. In this case, a group of phosphorylation sites in a given protein region contributes collectively to the modification of the protein, irrespective of the precise position of individual sites, through an aggregate property. Here we discuss these two types of regulation and examine how they affect the rate and patterns of protein phosphorylation evolution. We describe how the evolution of clusters of phosphorylation sites can be studied under the framework of complex traits evolution and stabilizing selection.
    Frontiers in Genetics 07/2014; 5:245. DOI:10.3389/fgene.2014.00245
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    • "Within a single protein, clusters of kinase target sites can act as a functional unit whereby the position of each site within the cluster might not be strongly constrained. This could be the case if the role of the modifications were to regulate the bulk electrostatics of a protein region (Strickfaden et al, 2007) or to achieve a non-linear regulatory outcome (K~ oivom€ agi et al, 2011). Phosphosites are often found in clusters within proteins (Schweiger & Linial, 2010; Christian et al, 2012) and the clustering of sites matching a kinase motif can serve as a predictor for kinase-target interactions further highlighting the functional importance of these clusters (Moses et al, 2007a). "
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    ABSTRACT: Protein post-translational modifications (PTMs) allow the cell to regulate protein activity and play a crucial role in the response to changes in external conditions or internal states. Advances in mass spectrometry now enable proteome wide characterization of PTMs and have revealed a broad functional role for a range of different types of modifications. Here we review advances in the study of the evolution and function of PTMs that were spurred by these technological improvements. We provide an overview of studies focusing on the origin and evolution of regulatory enzymes as well as the evolutionary dynamics of modification sites. Finally, we discuss different mechanisms of altering protein activity via post-translational regulation and progress made in the large-scale functional characterization of PTM function.
    Molecular Systems Biology 12/2013; 9(1):714. DOI:10.1002/msb.201304521 · 10.87 Impact Factor
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