AJP - Regulatory, Integrative and Comparative Physiology, Vol 250, Issue 6 1123-R1132, Copyright © 1986 by American Physiological Society
Regulation of interacting populations during endocytosis: models of growth factor-tumor promoter dynamics
M. Gex-Fabry and C. DeLisi
A model of growth factor-cell receptor interactions, including
internalization, sorting, recycling, and degradation and their modulation
by tumor promoters, is developed, analyzed, and tested. In keeping with
data and concepts based on a large number of systems, the main assumption
is that after receptor-ligand binding the complex associates with a second
membrane protein, localized in coated pits, and that this event is a
necessary condition for receptor-mediated endocytosis and subsequent
intracellular processes. As a consequence of the model, ligands having
distinct receptors interfere at the cell surface through competition
between their receptor complexes for a limited pool of coated pit proteins.
The utility of the model is illustrated by a detailed analysis of binding,
endocytosis, and degradation of epidermal growth factor (EGF) and their
modulation by phorbol esters. The analysis permits quantitative
characterization of the dynamics of the endocytic processes and leads to
the following conclusions. The Scatchard plot changes from linear to
nonlinear as the ratio of the number of coated pit proteins to the number
of receptors decreases. Competition between phorbol ester and EGF-bound
receptors for coated pit proteins predicts, in agreement with observation,
conversion of nonlinear EGF Scatchard plots to linear plots subsequent to
reincubation with phorbol esters. The postulated competition suggests a
local homology between the phorbol ester receptor and the EGF receptor.
Homologous and heterologous downregulations observed in numerous systems
are natural consequences of the model. Preincubation with the heterologous
ligand increases the time lag between ligand binding and lysosomal
degradation and alters intracellular sorting.
