EGFR & HER2 trafficking and signaling dynamics : experimental and modeling studies

EGFR and HER2 expression levels have distinguished themselves as important factors in contributing to various types of cancers including breast and ovarian cancers, but quantitative linkages between receptor expression levels and aberrant cell behaviors are not well understood. The ability to interpret and predict cell responses in a multi-parameter space will be vital in efforts to manipulate cell behavior for therapeutic purposes. HER2 acts as a co-receptor of the EGFR family of receptor tyrosine kinases. HER2 does not bind any known ligand, but plays an active signaling role following heterodimerization with a ligand-bound EGFR family receptor. EGFR family receptors undergo a dynamic process termed trafficking in which receptors and ligands are internalized and then either recycled to the surface or targeted for degradation. Trafficking is intimately connected to cell signaling by controlling the quantity and location of ligand-receptor complexes and is sensitive to disruption via the overexpression of the receptors involved. In this work, we quantitatively establish the role of HER2 and heterodimerization in EGFR trafficking and signaling. A hierarchy of mathematical models describing the trafficking behavior of EGFR and HER2 was developed at various levels of mechanistic detail. At the macroscopic level the trafficking of EGFR and HER2 fall into two regimes, one whose downregulation is sorting-limited (EGFR) and one whose downregulation is internalization-limited (HER2).

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2003

Author dc:creator

• Hendriks, Bart S. (Bart Sebastian), 1976-

Advisor dc:contributor.advisor

• Douglas A. Lauffenburger.

• Chemical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/17009

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/17009