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 Title: Growth-factor-induced mitogenesis: Trafficking determinants of the cellular response Author(s): Reddy, Cartikeya Chennuru Doctoral Committee Chair(s): Lauffenburger, Douglas A. Department / Program: Chemical and Biomolecular Engineering Discipline: Chemical Engineering Degree Granting Institution: University of Illinois at Urbana-Champaign Degree: Ph.D. Genre: Dissertation Subject(s): Biology, Cell Engineering, Biomedical Engineering, Chemical 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. Issue Date: 1996 Type: Text Language: English URI: http://hdl.handle.net/2142/21284 ISBN: 9780591200454 Rights Information: Copyright 1996 Reddy, Cartikeya Chennuru Date Available in IDEALS: 2011-05-07 Identifier in Online Catalog: AAI9712416 OCLC Identifier: (UMI)AAI9712416
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