Autocrine ligand binding to cell receptors. Mathematical analysis of competition by solution "decoys".
Autocrine ligands have been demonstrated to regulate cell proliferation, cell adhesion, and cell migration in a number of different systems and are believed to be one of the underlying causes of malignant cell transformation. Binding of these ligands to their cellular receptors can be compromised by diffusive transport of ligand away from the secreting cell. Exogenous addition of antibodies or solution receptors capable of competing with cellular receptors for these autocrine ligands has been proposed as a means of inhibiting autocrine-stimulated cell behavioral responses. Such "decoys" complicate cellular binding by offering alternative binding targets, which may also be capable of aiding or abating transport of the ligand away from the cell surface. We present a mathematical model incorporating autocrine ligand production and the presence of competing cellular and solution receptors. We elucidate effects of key system parameters including ligand diffusion rate, binding rate constants, cell density, and secretion rate on the ability of solution receptors to inhibit cellular receptor binding. Both plated and suspension cell systems are considered. An approximate analytical expression relating the key parameters to the critical concentration of solution "decoys" required for inhibition is derived and compared to the numerical calculations. We find that in order to achieve essentially complete inhibition of surface receptor binding, the concentration of decoys may need to be as much as four to eight orders of magnitude greater than the equilibrium disociation constant for ligand binding to surface receptors.
Forsten
K E
KE
Department of Chemical Engineering, University of Illinois, Urbana-Champaign 61801.
Lauffenburger
D A
DA
D001667:Binding, Competitive; D055592:Biophysical Phenomena; D001703:Biophysics; D007700:Kinetics; D008024:Ligands; D008433:Mathematics; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000378:metabolism*
D008024:Ligands; D011956:Receptors, Cell Surface