Growth-factor-induced mitogenesis: Trafficking determinants of the cellular response
Reddy, Cartikeya Chennuru
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https://hdl.handle.net/2142/21284
Description
Title
Growth-factor-induced mitogenesis: Trafficking determinants of the cellular response
Author(s)
Reddy, Cartikeya Chennuru
Issue Date
1996
Doctoral Committee Chair(s)
Lauffenburger, Douglas A.
Department of Study
Chemical and Biomolecular Engineering
Discipline
Chemical Engineering
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Engineering, Biomedical
Engineering, Chemical
Language
eng
Abstract
At the present time, growth factor stimulation of cell proliferation is conceptualized predominantly in terms of the initial binding event between the growth factor and its receptor. However, the dynamics of the cellular trafficking of growth factors and their receptors can be an important determinant of the cellular response to growth factor stimulation. We have explored this hypothesis using the epidermal growth factor (EGF) receptor regulation of fibroblast proliferation as a model system. The mitogenic responses elicited by EGF, TGF$\alpha$, and an EGF-variant (Y13G) which possess different surface binding affinities and altered intracellular fates, are compared in distinct experimental scenarios, with or without ligand replenishment. Our results show that cellular uptake and trafficking of these ligands modulates the mitogenic response via a balance between receptor binding and concomitant mitogenic signaling from activated complexes, and the subsequent attenuation of signal due to internalization and degradation of growth factors and their receptors. Specifically, we have shown that Y13G, which has a binding affinity that is 50-fold lower than EGF and TGF$\alpha$, can be a better mitogen owing to its favorable trafficking properties. Therefore the relative potencies of these ligands cannot be predicted based on surface binding affinities alone. The dynamics of ligand and receptor accessibility as determined in conjunction with cellular properties and assay parameters are important determinants of growth factor potency.
Our results demonstrate that ligand re-engineering--the optimization of the molecular interaction between growth factor and receptor--requires systemic integration of processes from the initial molecular recognition event to the ultimate cell response.
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