14 April 2006
Growth factor binding to cognate surface receptors induces receptor dimerization, autophosphorylation and internalization via coated pits. Reports that many growth factor receptors remain phosphorylated and continue to signal after internalization revises the traditional view that endocytosis downregulates growth factor signaling. It is therefore important to parse the factors that govern the persistence and amplitude of endosomal signals. This is a challenging experimental problem. In this talk I will present our recent analysis of a kinetic model of EGFR internalization and sorting and argue that the stability of endosomal complexes can be described by a single dimensionless parameter that depends on three primary independent factors: the endosomal dissociation constant, total endosomal volume and number of endosomal receptors. I will discuss the biological and clinical implications of this result and if time allows also discuss the important issue of model distinguishability.
Our results were obtained using a combination of controlled approximation (see reprints) and verified numerically.
A R Tzafriri, D Wu & E R Edelman, "Analysis of compartmental models of ligand induced endocytosis", J Theor Biol 229:127-138, 2004. PubMed PDF
A R Tzafriri, "Michaelis-Menten kinetics at high enzyme concentrations", Bull Math Biol 65:1111-29 2002. PubMed PDF
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