Parameter space exploration within dynamic simulations of signaling networks.

We started offering an introduction to very basic aspects of molecular biology, for the reader coming from computer sciences, information technology, mathematics. Similarly we offered a minimum of information about pathways and networks in graph theory, for a reader coming from the bio-medical sector. At the crossover about the two different types of expertise, we offered some definition about Systems Biology. The core of the article deals with a Molecular Interaction Map (MIM), a network of biochemical interactions involved in a small signaling-network sub-region relevant in breast cancer. We explored robustness/sensitivity to random perturbations. It turns out that our MIM is a non-isomorphic directed graph. For non physiological directions of propagation of the signal the network is quite resistant to perturbations. The opposite happens for biologically significant directions of signal propagation. In these cases we can have no signal attenuation, and even signal amplification. Signal propagation along a given pathway is highly unidirectional, with the exception of signal-feedbacks, that again have a specific biological role and significance. In conclusion, even a relatively small network like our present MIM reveals the preponderance of specific biological functions over unspecific isomorphic behaviors. This is perhaps the consequence of hundreds of millions of years of biological evolution.

[1]  D. Gillespie Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[2]  A. Gibbons Algorithmic Graph Theory , 1985 .

[3]  G A Colditz,et al.  The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. , 1995, The New England journal of medicine.

[4]  J. Tyson,et al.  Chemical kinetic theory: understanding cell-cycle regulation. , 1996, Trends in biochemical sciences.

[5]  S. Leibler,et al.  Robustness in simple biochemical networks , 1997, Nature.

[6]  B. Kholodenko,et al.  Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor* , 1999, The Journal of Biological Chemistry.

[7]  H V Westerhoff,et al.  Why cytoplasmic signalling proteins should be recruited to cell membranes. , 2000, Trends in cell biology.

[8]  T. Ideker,et al.  A new approach to decoding life: systems biology. , 2001, Annual review of genomics and human genetics.

[9]  E. Hairer,et al.  Solving Ordinary Differential Equations II: Stiff and Differential-Algebraic Problems , 2010 .

[10]  H. Kitano,et al.  Computational systems biology , 2002, Nature.

[11]  G. Church,et al.  Analysis of optimality in natural and perturbed metabolic networks , 2002 .

[12]  L. Hood Systems biology: integrating technology, biology, and computation , 2003, Mechanisms of Ageing and Development.

[13]  Janine E. Trempy,et al.  Fundamental Bacterial Genetics , 2003 .

[14]  C. Downes,et al.  PTEN function: how normal cells control it and tumour cells lose it. , 2004, The Biochemical journal.

[15]  John N Weinstein,et al.  Molecular Interaction Maps--A Diagrammatic Graphical Language for Bioregulatory Networks , 2004, Science's STKE.

[16]  B N Kholodenko,et al.  Signal processing at the Ras circuit: what shapes Ras activation patterns? , 2004, Systems biology.

[17]  G. Church,et al.  Modular epistasis in yeast metabolism , 2005, Nature Genetics.

[18]  G. Hampton,et al.  A phosphoproteomic analysis of the ErbB2 receptor tyrosine kinase signaling pathways. , 2006, Biochemistry.

[19]  E. Tokunaga,et al.  Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma , 2007, Breast Cancer Research and Treatment.

[20]  B. Kholodenko Cell-signalling dynamics in time and space , 2006, Nature Reviews Molecular Cell Biology.

[21]  J. Weinstein,et al.  Molecular interaction maps of bioregulatory networks: a general rubric for systems biology. , 2005, Molecular biology of the cell.

[22]  Boris N Kholodenko,et al.  Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops* , 2006, Journal of Biological Chemistry.

[23]  J. Weinstein,et al.  Depicting combinatorial complexity with the molecular interaction map notation , 2006, Molecular systems biology.

[24]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[25]  David S Wishart,et al.  Computational systems biology in drug discovery and development: methods and applications. , 2007, Drug discovery today.

[26]  F. Bruggeman,et al.  The nature of systems biology. , 2007, Trends in microbiology.

[27]  Douglas A. Lauffenburger,et al.  Systems Biology: International Research and Development , 2007 .

[28]  Igor Goryanin,et al.  The impact of the regulatory design on the response of epidermal growth factor receptor‐mediated signal transduction towards oncogenic mutations , 2007, The FEBS journal.

[29]  B. Kholodenko,et al.  Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses , 2007, Molecular systems biology.

[30]  C. Yeang,et al.  Combinatorial patterns of somatic gene mutations in cancer , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  S. Ng,et al.  Phosphatidylinositol 3-Kinase Signaling Does Not Activate the Wnt Cascade , 2009, The Journal of Biological Chemistry.

[32]  Jens Timmer,et al.  Systems-level interactions between insulin–EGF networks amplify mitogenic signaling , 2009, Molecular systems biology.

[33]  D. Lauffenburger,et al.  Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data , 2009, Molecular systems biology.

[34]  D. Wilkinson Stochastic modelling for quantitative description of heterogeneous biological systems , 2009, Nature Reviews Genetics.

[35]  Boris N. Kholodenko,et al.  Ligand-Specific c-Fos Expression Emerges from the Spatiotemporal Control of ErbB Network Dynamics , 2010, Cell.

[36]  D. Voskas,et al.  Does GSK-3 provide a shortcut for PI3K activation of Wnt signalling? , 2010, F1000 biology reports.

[37]  S Parodi,et al.  Dynamic simulations of pathways downstream of ERBB-family, including mutations and treatments: concordance with experimental results. , 2010, Current cancer drug targets.

[38]  Ruth Nussinov,et al.  A formal MIM specification and tools for the common exchange of MIM diagrams: an XML-Based format, an API, and a validation method , 2011, BMC Bioinformatics.

[39]  Edited Sir John Kendrew The Encyclopedia of molecular , 2012 .

[40]  C. De Ambrosi,et al.  A multi-scale approach to colorectal cancer: from a biochemical- interaction signaling-network level, to multi-cellular dynamics of malignant transformation. Interplay with mutations and onco-protein inhibitor drugs. , 2012, Current cancer drug targets.