Recurrent design patterns in the feedback regulation of the mammalian signalling network

Biochemical networks are characterized by recurrent patterns and motifs, but the design principles underlying the dynamics of the mammalian intracellular signalling network remain unclear. We systematically analysed decay rates of 134 signalling proteins and investigated their gene expression profiles in response to stimulation to get insights into transcriptional feedback regulation. We found a clear separation of the signalling pathways into flexible and static parts: for each pathway a subgroup of unstable signal inhibitors is transcriptionally induced upon stimulation, while the other constitutively expressed signalling proteins are long‐lived. Kinetic modelling suggests that this design principle allows for swift feedback regulation and establishes latency phases after signalling, and that it might be an optimal design due to a trade‐off between energy efficiency and flexibility.

[1]  S Udenfriend,et al.  Increased turnover of arterial collagen in hypertensive rats. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Agard,et al.  Turnover of regulatory subunit of cyclic AMP-dependent protein kinase in S49 mouse lymphoma cells. Regulation by catalytic subunit and analogs of cyclic AMP. , 1981, The Journal of biological chemistry.

[3]  J. Pouysségur,et al.  Hirudin, a probe to analyze the growth-promoting activity of thrombin in fibroblasts; reevaluation of the temporal action of competence factors. , 1982, Biochemical and biophysical research communications.

[4]  T. Y. Shih,et al.  Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs , 1984, Molecular and cellular biology.

[5]  G. Carpenter,et al.  Epidermal growth factor: the receptor and its function. , 1989, BioFactors.

[6]  C. Heldin,et al.  Effect of receptor kinase inactivation on the rate of internalization and degradation of PDGF and the PDGF beta-receptor , 1991, The Journal of cell biology.

[7]  Hong Sun,et al.  MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo , 1993, Cell.

[8]  Repression of platelet-derived growth factor beta-receptor expression by mitogenic growth factors and transforming oncogenes in murine 3T3 fibroblasts. , 1995, Molecular and cellular biology.

[9]  R. Aebersold,et al.  Characterization of Lnk , 1997, The Journal of Biological Chemistry.

[10]  K. Luo,et al.  Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. , 1999, Science.

[11]  J C Reed,et al.  Caspase-9 Can Be Activated without Proteolytic Processing* , 1999, The Journal of Biological Chemistry.

[12]  A. Cuddihy,et al.  Upregulation of STAT1 protein in cells lacking or expressing mutants of the double-stranded RNA-dependent protein kinase PKR. , 1999, European journal of biochemistry.

[13]  M. Karin,et al.  Stress-induced JNK Activation Is Independent of Gadd45 Induction* , 1999, The Journal of Biological Chemistry.

[14]  R. Weinberg,et al.  SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. Heinrich,et al.  Different protein turnover of interleukin-6-type cytokine signalling components. , 1999, European journal of biochemistry.

[16]  Francisca Vazquez,et al.  Phosphorylation of the PTEN Tail Regulates Protein Stability and Function , 2000, Molecular and Cellular Biology.

[17]  T. Hughes,et al.  Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global gene expression profiles. , 2000, Science.

[18]  R. Albert,et al.  The large-scale organization of metabolic networks , 2000, Nature.

[19]  W. Wieser,et al.  Hierarchies of ATP-consuming processes: direct compared with indirect measurements, and comparative aspects. , 2001, The Biochemical journal.

[20]  E. Sontag Protein phosphatase 2A: the Trojan Horse of cellular signaling. , 2001, Cellular signalling.

[21]  R. Pulido,et al.  The Tumor Suppressor PTEN Is Phosphorylated by the Protein Kinase CK2 at Its C Terminus , 2001, The Journal of Biological Chemistry.

[22]  M. Camps,et al.  The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP kinases. , 2001, Journal of cell science.

[23]  C. Reilly,et al.  Genome-wide analysis of mRNA decay in resting and activated primary human T lymphocytes. , 2002, Nucleic acids research.

[24]  C. Rao,et al.  Control, exploitation and tolerance of intracellular noise , 2002, Nature.

[25]  D. Lauffenburger,et al.  Autocrine loops with positive feedback enable context-dependent cell signaling. , 2002, American journal of physiology. Cell physiology.

[26]  T. Kudoh,et al.  Identification of Sef, a novel modulator of FGF signalling , 2002, Nature Cell Biology.

[27]  M. Kohno,et al.  Prolonged Nuclear Retention of Activated Extracellular Signal-regulated Kinase 1/2 Is Required for Hepatocyte Growth Factor-induced Cell Motility* , 2002, The Journal of Biological Chemistry.

[28]  A. Ashworth,et al.  Differential effects of stress stimuli on a JNK-inactivating phosphatase , 2002, Oncogene.

[29]  Reinhart Heinrich,et al.  Mathematical models of protein kinase signal transduction. , 2002, Molecular cell.

[30]  M. Magnasco,et al.  Decay rates of human mRNAs: correlation with functional characteristics and sequence attributes. , 2003, Genome research.

[31]  J. Gregg,et al.  Allele-specific Holliday junction formation: a new mechanism of allelic discrimination for SNP scoring. , 2003, Genome research.

[32]  M. Tresini,et al.  Metabolic stabilization of MAP kinase phosphatase-2 in senescence of human fibroblasts. , 2003, Experimental cell research.

[33]  David Loegering,et al.  Components of the Cell Death Machine and Drug Sensitivity of the National Cancer Institute Cell Line Panel , 2004, Clinical Cancer Research.

[34]  H. Sauro,et al.  Quantitative analysis of signaling networks. , 2004, Progress in biophysics and molecular biology.

[35]  T. Hunter,et al.  Inappropriate Activation of the TSC/Rheb/mTOR/S6K Cassette Induces IRS1/2 Depletion, Insulin Resistance, and Cell Survival Deficiencies , 2004, Current Biology.

[36]  E. Nishida,et al.  Sef is a spatial regulator for Ras/MAP kinase signaling. , 2004, Developmental cell.

[37]  S. Kasif,et al.  Identification of Transcription Factor Binding Sites Upstream of Human Genes Regulated by the Phosphatidylinositol 3-Kinase and MEK/ERK Signaling Pathways* , 2004, Journal of Biological Chemistry.

[38]  Ronald N Germain,et al.  Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses , 2005, PLoS biology.

[39]  J. Timmer,et al.  Design principles of a bacterial signalling network , 2005, Nature.

[40]  Edwin Wang,et al.  Self-organization of gene regulatory network motifs enriched with short transcript's half-life transcription factors , 2005, q-bio/0504025.

[41]  César Nombela,et al.  Protein phosphatases in MAPK signalling: we keep learning from yeast , 2005, Molecular microbiology.

[42]  Jan Lankelma,et al.  Principles behind the multifarious control of signal transduction , 2004, The FEBS journal.

[43]  C. V. Suresh Babu,et al.  Method development and measurements of endogenous serine/threonine Akt phosphorylation using capillary electrophoresis for systems biology , 2005, Electrophoresis.

[44]  Konstantinos Michalodimitrakis,et al.  Noise in transcription negative feedback loops: simulation and experimental analysis , 2006, Molecular systems biology.

[45]  E. O’Shea,et al.  Quantification of protein half-lives in the budding yeast proteome , 2006, Proceedings of the National Academy of Sciences.

[46]  Alexandros Tzatsos,et al.  Nutrients Suppress Phosphatidylinositol 3-Kinase/Akt Signaling via Raptor-Dependent mTOR-Mediated Insulin Receptor Substrate 1 Phosphorylation , 2006, Molecular and Cellular Biology.

[47]  U. Alon Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[48]  Sebastian Thiem,et al.  Positioning of chemosensory clusters in E. coli and its relation to cell division , 2007, The EMBO journal.

[49]  T. Meng,et al.  Several Dual Specificity Phosphatases Coordinate to Control the Magnitude and Duration of JNK Activation in Signaling Response to Oxidative Stress* , 2007, Journal of Biological Chemistry.

[50]  P. Bastiaens,et al.  Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate , 2007, Nature Cell Biology.

[51]  Nils Blüthgen,et al.  Specialization, Constraints, and Conflicting Interests in Mutualistic Networks , 2007, Current Biology.

[52]  Eytan Domany,et al.  A module of negative feedback regulators defines growth factor signaling , 2007, Nature Genetics.

[53]  Jerome T. Mettetal,et al.  The Frequency Dependence of Osmo-Adaptation in Saccharomyces cerevisiae , 2008, Science.

[54]  Necmettin Yildirim,et al.  β2-Adrenergic Receptor Signaling and Desensitization Elucidated by Quantitative Modeling of Real Time cAMP Dynamics* , 2008, Journal of Biological Chemistry.