Superagonistic activation of ErbB-1 by EGF-related growth factors with enhanced association and dissociation rate constants

Kinetic Characterization by Surface Plasmon Resonance-Based Biosensors: Principle and Emerging Trends

“…A comparison of data presented in Fig. 2f to those in De Crescenzo et al 11 or in Lenferink et al 32 (corresponding to monomeric EGF receptor ectodomain/EGF interactions) illustrates how an avidity situation drastically modifies binding profile.…”

“…13 For several macromolecular interactions, correlations between the biological potencies of biomolecules and their kinetics of interactions with their partners have been clearly established. For example, in a study performed by Lenferink et al, 32 various mutants of the transforming growth factor a (TGF-a) were characterized for their kinetics of binding to the ectodomain of their receptor as well as for their agonistic potency in in vitro cell assays. It was reported that, for some mutants, differences in kinetics correlated to marked differences in biological outcomes, while compensating each other to result in similar affinities.…”

Discovery of Improved EGF Agonists Using a Novel In Vitro Screening Platform

“…Despite extensive studies of the EGF/EGFR system, the mechanisms that govern biological potency remain unclear. 12,[31][32][33][34][35][36] Many functional characteristics, such as binding affinity, on and off rates, and affinities at low pH, are hypothesized to affect activity. Mutants such as T10 and T78, which have three and eight nonredundant mutations, respectively (Table 1), will help to identify the principles relating mutations in primary sequence to these functional characteristics, as well as the contributions of these characteristics to overall biological potency.…”

Ligand depletion negatively controls the mitogenic activity of epidermal growth factor

“…In previous studies we have shown that E4T, a superagonistic chimera composed of EGF sequences N-terminal and TGFa sequences C-terminal of the fourth cysteine, shows similar binding affinity for ErbB1 as EGF and TGFa, but induces mitogenic activity at already a 10-fold lower concentration than the wild-type ligands of which it is composed [27]. These superagonists are characterised by enhanced association and dissociation rate constants [33], coupled to reduced cellular uptake and degradation [34]. Fig.…”