Role of the interaction of proHB-EGF with heparan sulfate proteoglycans
Name
701557801-MIT.pdf
Description
Full printable version
Size
12.89 MB
Format
Adobe PDF
Checksum (MD5)
341b65bc28fe5073f14fd2dfbf034ab0
Author(s)
Prince, Robin Neely
Advisor(s)
Douglas A. Lauffenburger and Richard T. Lee.
Alternative Title
Role of the interaction of pro heparin-binding epidermal growth factor-like growth factor with HSPGs
Date Issued
2009
Publisher
Massachusetts Institute of Technology
Abstract
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) exhibits activity as a juxtacrine, paracrine, and autocrine ligand for the epidermal growth factor receptor (EGFR), and possesses the ability to bind heparan sulfate proteoglycans (HSPGs). The interaction of HB-EGF with HSPGs has been previously studied only with the soluble (autocrine/paracrine) form of the protein (sHB-EGF), produced after proteolytic cleavage of the transmembrane form (proHB-EGF) from the cell surface. It was hypothesized that HSPGs interact with proHB-EGF in ways that could alter behavior of the transmembrane form of this ligand and consequent processes. Using an engineered form of proHB-EGF that allowed for independent tracking of the extracellular domain and the C-terminal tail, proHB-EGF was observed primarily at sites of cell-cell contact. However, a dramatic change in this localization was observed upon the addition of exogenous heparin, heparan sulfate, heparinase III or mutation of the heparin-binding domain of proHB-EGF, suggesting that an interaction with HSPGs is responsible for localizing proHB-EGF to sites of cell-cell contact. Further studies in wild-type CHO-Ki cells and heparan sulfate deficient CHOpgsD-677 cells demonstrated that a trans interaction between proHB-EGF and HSPGs on neighboring cells was responsible for this localization. Additionally, this interaction inhibited proteolytic processing of the ligand, as heparin and mutation of the heparin-binding domain increased the amount of sHB-EGF accumulated in the media.
Description
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2009.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 106-116).
Subjects
Biological Engineering.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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