The SH2 domain-containing protein-tyrosine phosphatase Shp2 is an important regulator of intracellular signaling pathways. In this work we present a computational, rule based model, which simulates the combinatorial interactions of this protein to its phospho-tyrosine substrates on signaling receptors. The two SH2-domains of Shp2 have differential role in regulating the catalytic potency of Shp2. Besides their respective contribution in allosteric enzymatic activation, these two domains target Shp2 to signaling receptors in different extents. Our kinetic model integrates these two competing effects by considering the intra- and intermolecular interactions of the Shp2 SH2 domains and catalytic site as well as the effect of Shp2 phosphorylation. This apparently simplistic model is comprised of over a thousand molecular species due to the complex network of binding and phosphorylation states of the molecules. To our knowledge, this is the first kinetic model to fully consider the modular, multifunctional structure of a signaling protein.

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