Win, Lose, or Tie: Mathematical Modeling of Ligand Competition at the Cell–Extracellular Matrix Interface

Abstract

Integrin transmembrane proteins conduct mechanotransduction at the cell–extracellular matrix (ECM) interface. This process is central to cellular homeostasis and therefore is particularly important when designing instructive biomaterials and organoid culture systems. Previous studies suggest that fine-tuning the ECM composition and mechanical properties can improve organoid development. Toward the bigger goal of fully functional organoid development, we hypothesize that resolving the dynamics of ECM–integrin interactions will be highly instructive. To this end, we developed a mathematical model that enabled us to simulate three main interactions, namely integrin activation, ligand binding, and integrin clustering. Different from previously published computational models, we account for the binding of more than one type of ligand to the integrin. This competition between ligands defines the fate of the system. We have demonstrated that an increase in the initial concentration of ligands does not ensure an increase in the steady state concentration of ligand-bound integrins. The ligand with higher binding rate occupies more integrins at the steady state than does the competing ligand. With cell type specific, quantitative input on integrin-ligand binding rates, this model can be used to develop instructive cell culture systems.

Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program

“…Further, the affinity of endogenous Hh ligands for PTCH2 is lower than what was exhibited by TRP120 (4.40 ± 1.5 nM). A recent study demonstrates that ligands with higher binding affinity disable lower affinity ligands from binding their receptor [ 59 ]. Thus, TRP120 may have a higher binding affinity to PTCH2 to provide a competitive advantage over endogenous Hh ligands.…”

Thyroid Hormone Disruption by Organophosphate Esters Is Mediated by Nuclear/Membrane Thyroid Hormone Receptors: In Vitro, In Vivo, and In Silico Studies

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Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program

“…Further, the affinity of endogenous Hh ligands for PTCH2 is strong, but surprisingly weaker than what was exhibited by TRP120 (4.40 ± 1.5 nM). A recent study demonstrates that ligands with higher binding affinity disable lower affinity ligands from binding their receptor (58). Thus, TRP120 may have a higher binding affinity to PTCH2 to provide a competitive advantage over endogenous Hh ligands.…”