Systems biology analysis of G protein and MAP kinase signaling in yeast

Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Oncogene (Impact Factor: 8.46). 06/2007; 26(22):3254-66. DOI: 10.1038/sj.onc.1210416
Source: PubMed


Approximately a third of all drugs act by binding directly to cell surface receptors coupled to G proteins. Other drugs act indirectly on these same pathways, for example, by inhibiting neurotransmitter reuptake or by blocking the inactivation of intracellular second messengers. These drugs have revolutionized the treatment of human disease. However, the complexity of G protein signaling mechanisms has significantly hampered our ability to identify additional new drug targets. Moreover, today's molecular pharmacologists are accustomed to working on narrowly focused problems centered on a single protein or enzymatic process. Here we describe emerging efforts in yeast aimed at identifying proteins and processes that modulate the function of receptors, G proteins and MAP kinase effectors. The scope of these efforts is far more systematic, comprehensive and quantitative than anything attempted previously, and includes integrated approaches in genetics, proteomics and computational biology.

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Available from: Henrik G Dohlman, Jun 27, 2014
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    • "It describes an organism's response to an external perturbation by returning state variables to their original values before perturbation. For example, perfect adaptation has been reported in bacterial (e.g., E. coli) chemotaxis (Berg and Tedesco, 1975; Alon et al., 1999; Yi et al., 2000; Hansen et al., 2008), osmotic-stress adaptations (Muzzey et al., 2009), and MAP-kinase regulation (Hao et al., 2007; Mettetal et al., 2008). Such perfect adaption behaviors are thought to be introduced through a time integral on the " controlled variable " in the network , which corresponds to a specific control system structure, i.e., an integral feedback control (Csete and Doyle, 2002). "
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    ABSTRACT: Living organisms persist by virtue of complex interactions among many components organized into dynamic, environment-responsive networks that span multiple scales and dimensions. Biological networks constitute a type of Information and Communication Technology (ICT): they receive information from the outside and inside of cells, integrate and interpret this information, and then activate a response. Biological networks enable molecules within cells, and even cells themselves, to communicate with each other and their environment. We have become accustomed to associating brain activity – particularly activity of the human brain – with a phenomenon we call “intelligence”. Yet, four billion years of evolution could have selected networks with topologies and dynamics that confer traits analogous to this intelligence, even though they were outside the intercellular networks of the brain. Here, we explore how macromolecular networks in microbes confer intelligent characteristics, such as memory, anticipation, adaptation and reflection and we review current understanding of how network organization reflects the type of intelligence required for the environments in which they were selected. We propose that, if we were to leave terms such as “human” and “brain” out of the defining features of “intelligence”, all forms of life – from microbes to humans – exhibit some or all characteristics consistent with “intelligence”. We then review advances in genome-wide data production and analysis, especially in microbes, that provide a lens into microbial intelligence and propose how the insights derived from quantitatively characterizing biomolecular networks may enable synthetic biologists to create intelligent molecular networks for biotechnology, possibly generating new forms of intelligence, first in silico and then in vivo.
    Frontiers in Microbiology 07/2014; 5:379. DOI:10.3389/fmicb.2014.00379 · 3.99 Impact Factor
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    • "A number of studies have provided mathematical models of ERK activation by EGF (Kholodenko et al, 1999; Orton et al, 2005; Borisov et al, 2009; Kholodenko et al, 2010), including the dynamics of transient and sustained ERK activation (Sasagawa et al, 2005; Nakakuki et al, 2010). ERK response to a G protein-coupled 7TMR in yeast and mammals (Hao et al, 2007; Csercsik et al, 2008) as well as the role of GRK in the desensitization, internalization and recycling of the b 2 adrenergic receptor (b2AR) (Violin et al, 2008; Vayttaden et al, 2010) have also been modeled. In addition, a number of other studies have modeled different aspects of 7TMRs signaling, including calcium signaling (see Linderman, 2009 for a recent review). "
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    ABSTRACT: Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β-arrestins, whose recruitment to the activated receptor is regulated by G protein-coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal-regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT(1A)R) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)-based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well-established function in the desensitization of G-protein activation, GRK2 exerts a strong negative effect on β-arrestin-dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2-dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT(1A)R, and HEK293 cells expressing other 7TMRs.
    Molecular Systems Biology 06/2012; 8(1):590. DOI:10.1038/msb.2012.22 · 10.87 Impact Factor
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    • "Sho1p has the potential to form homo-oligomers (Table S1) (Hao et al., 2007). Once exceeding a critical concentration, these oligomers might condense the isolated interaction states into a single net (Figure 8C). "
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    ABSTRACT: A molecular understanding of cytokinesis requires the detailed description of the protein complexes that perform central activities during this process. The proteins Hof1p, Cyk3p, Inn1p, and Myo1p each represent one of the four genetically defined and partially complementing pathways of cytokinesis in the yeast Saccharomyces cerevisiae. Here we show that the osmosensor Sho1p is required for correct cell-cell separation. Shortly before cytokinesis Sho1p sequentially assembles with Hof1p, Inn1p, and Cyk3p, into a complex (HICS-complex) that might help to connect the membrane with the actin-myosin ring. The HICS-complex is formed exclusively via the interactions between three SH3 domains located in Cyk3p, Hof1p, and Sho1p, and five acceptor sites found in Cyk3p, Hof1p, and Inn1p. Due to the overlapping binding specificities of its members the HICS-complex is best described as ensembles of isomeric interaction states that precisely coordinate the different functions of the interactors during cytokinesis.
    Journal of Cell Science 05/2012; 125(17). DOI:10.1242/jcs.105320 · 5.43 Impact Factor
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