Quantitative studies of EGFR autocrine induced cell signaling and migration
Name
182579616-MIT.pdf
Description
Full printable version
Size
13.5 MB
Format
Adobe PDF
Checksum (MD5)
62a45ff2a64ce8500aa089280a685a9b
Author(s)
Joslin, Elizabeth Jane
Advisor(s)
Douglas A. Lauffenburger.
Alternative Title
Quantitative studies of epidermal growth factor receptor autocrine induced cell signaling and migration
Date Issued
2007
Publisher
Massachusetts Institute of Technology
Abstract
Epidermal growth factor (EGF) receptor autocrine and/or paracrine signaling plays an important role in normal epithelial cell proliferation, survival, adhesion and migration. Aberrant expression of the EGF receptor and its cognate ligands have been implicated in various types of cancers, hence EGF receptor autocrine activation is thought to also be involved in tumorigenesis. EGF family ligands are synthesized as membrane-anchored proteins requiring proteolytic release to form the mature soluble, receptor-binding factor. Despite the pathophysiological importance of autocrine systems, how protease-mediated ligand release quantitatively influences receptor-mediated signaling and consequent cell behavior is poorly understood. Therefore, we explored the relationship between autocrine EGF release rate and receptor-mediated ERK activation and migration in human mammary epithelial cells. A quantitative spectrum of EGF release rates was achieved using chimeric EGF ligand precursors modulated by the addition of the metalloprotease inhibitor batimastat. We found that ERK activation increased with increasing ligand release rates despite concomitant EGF receptor downregulation.
(cont.) Cell migration speed depended linearly on the steady-state phospho-ERK level, but was much greater for autocrine compared to exogenous stimulation. In contrast, cell proliferation rates were constant across the various treatment conditions. In addition, we investigated an EGFR-mediated positive feedback through ERK that stimulated a 4-fold increase in release rate of our TGFa based construct. Thus, in these cells, ERK-mediated migration stimulated by EGF receptor signaling is most sensitively regulated by autocrine ligand control mechanisms.
Description
Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2007.
Includes bibliographical references.
Subjects
Biological Engineering Division.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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