Lucarelli_TGFb_2017

Smad-Complex formation model in Hepa1.6

The model definition files are found in the folder Examples/Lucarelli_TGFb_2017

Model version 1: “TGFb_ComplexModel_ModelSelection_L1”: Model used for selection of complexes via L1-penalization

• 21 parameters
• TGFb binds and directly activates receptors
• Active receptors phosphorylate Smad2 and Smad3
• Two-step activation with backward reaction: Smad <-> pSmad <-> ppSmad with the same rates for Smad2 and Smad3
• Each complex has its own association rate, only ppSmad2 and ppSmad3 can form a complex
• Dephosphorylation of Smads directly induces dissociation of the complexes
• The dephosphorylation rates depend on the ppSmads (Smad2 or Smad3) and not on the complex in which as ppSmad occurs
• Smad2 and Smad3 can only form complexes after activation
• All 10 possible complexes formed by different trimer-combinations of Smad2, Smad3 and Smad4
• Initial values: only unphosphorylated Smads occur, complexes of unphosphorylated complexes are in the steady state

Model version 2: “ TGFb_ComplexModel_withGenes”: Model used for linking the identified three important complex to gene expression

• 117 parameters
• This model contains individual activation AND inhibition parameters to all possible gene targets
• Not required complexes have production rates = 0
• inits of Smads S2, S3, S4 are termed S2tot, S3tot, S4tot

Model version 3: “TGFb_ComplexModel_withGenes_Reduced”: Model verion 2 reduced by unnecessary inhibition/activation

• activation/inhibition parameters which are statistically in agreement with zero are set to zero (but still in the model)

Further technical comments

• If compiling time is an issue: Use compiler without code-optimization, e.g. with option -O0 or \od

If you refit the data using another software, please consider fitting of errors and the Bessel-correction.

Literature

The model has been published in [1]. Further details can be found there.

[1] Philippe Lucarelli, Marcel Schilling, Clemens Kreutz, Artyom Vlasov, Martin E. Boehm, Nao Iwamoto, Bernhard Steiert, Susen Lattermann, Marvin Wasch, Markus Stepath, Matthias S. Matter, Mathias Heikenwalder, Katrin Hoffmann, Daniela Deharde, Georg Damm, Daniel Seehofer, Maria Muciek, Norbert Gretz, Wolf D. Lehmann, Jens Timmer and Ursula Klingmueller Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression, Cell Systems, 2017, https://doi.org/10.1016/j.cels.2017.11.010