A Global Protein Kinase and Phosphatase Interaction Network in Yeast

Centre for Systems Biology, Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada.
Science (Impact Factor: 33.61). 05/2010; 328(5981):1043-6. DOI: 10.1126/science.1176495
Source: PubMed

ABSTRACT The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation.
We identified a kinase and phosphatase interaction (KPI) network of 1844 interactions in budding yeast by mass spectrometric
analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions.
Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated
protein kinase signaling, the DNA damage response, and metabolism, whereas interactions of the target of rapamycin complex
1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions
cross-connects the proteome and may serve to coordinate diverse cellular responses.

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Available from: Jeff Sharom, Sep 26, 2015
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    • "In this context, it is noteworthy that treatment of yeast cells with the TORC1 inhibitor rapamycin specifically increases ubiquitylation of Npr2. Moreover, all subunits of the SEA complex (except for Sec13) appear to be phosphorylated (Albuquerque et al., 2008; Breitkreutz et al., 2010; Spielewoy et al., 2010) and ubiquitylated (Hitchcock "
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    ABSTRACT: Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 - the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 05/2015; 128(12). DOI:10.1242/jcs.168922 · 5.43 Impact Factor
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    • "Subsequent studies in yeast also characterized more factors and also signaling pathways such as RAS2 and the TOR signaling pathway (Butow and Avadhani, 2004; Kirchman et al., 1999; Liu and Butow, 2006) (Table 1). The TOR pathway has also being linked to Rtg proteins in the context of retrograde signaling (Breitkreutz et al., 2010; Dilova et al., 2004; Dilova et al., 2002; Giannattasio et al., 2005; Komeili et al., 2000). Furthermore, yeast studies have shown that dysfunctional mitochondria inhibit TORC1 (Kawai et al., 2011). "
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    ABSTRACT: Mitochondria are critical metabolic hubs in which catabolic and anabolic cellular processes converge and are integrated. To perform their function, mitochondria also need to respond to signals that monitor their function and send continuous feedback to the nucleus and other organelles to trigger the required expression programs (for example, stabilization of hypoxia-inducible factor 1-α). Unsurprisingly, mitochondrial dysfunction results in wide range of disorders. Understanding how cells adapt to changes in mitochondrial function is critical for the evaluation of mitochondrial disorders and the development of potential treatments. Each type of mitochondrial dysfunction results in a unique transcriptional response. Here we review the role of nuclear-encoded factors in the response to changes in mitochondrial function and discuss their relevance to metabolic homeostasis, outlining the diverse and complex ways in which nuclei adapt to maintain mitochondrial homeostasis. Copyright © 2015. Published by Elsevier Ltd.
    The International Journal of Biochemistry & Cell Biology 02/2015; 63. DOI:10.1016/j.biocel.2015.01.026 · 4.05 Impact Factor
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    • "In some cases, pathway crosstalk may be sustained by single proteins [13] through molecular switches provided by post-translational modifications. Namely, different phosphorylation events may lead to inhibition or activation of the target protein and consequently potentially inhibit one pathway and activate another. "
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    ABSTRACT: Cellular fate depends on the spatiotemporal separation and integration of signaling processes that can be provided by phosphorylation events. In this study, we identify the crucial points in signaling crosstalk that can be triggered by discrete phosphorylation events on a single target protein. We integrated the data on individual human phosphosites with the evidence on their corresponding kinases, the functional consequences of phosphorylation on activity of the target protein and corresponding pathways. Our results show that there is a substantial fraction of phosphosites that can play critical roles in crosstalk between alternative and redundant pathways and regulatory outcome of phosphorylation can be linked to a type of phosphorylated residue. These regulatory phosphosites can serve as hubs in the signal flow and their functional roles are directly connected to their specific properties. Namely, phosphosites with similar regulatory functions are phosphorylated by the same kinases and participate in regulation of similar biochemical pathways. Such sites are more likely to cluster in sequence and space unlike sites with antagonistic outcomes of their phosphorylation on a target protein. In addition, we found that in silico phosphorylation of sites with similar functional consequences has comparable outcomes on a target protein stability. An important role of phosphorylation sites in biological crosstalk is evident from the analysis of their evolutionary conservation.
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