Living cells keep sensing the changes in their environments, mostly, via cell surface receptors for different ligands. Attachment-dependent cells are sensitive to alterations in extracellular matrix (ECM). ECM is not only required for cell survival, but also prerequisite for epidermal growth factor (EGF) to stimulate cell proliferation. The receptors for the majority of ECM components are integrins and the receptor for EGF is EGF receptor (EGFR). When bound by their ligands, integrins and EGFR induce signal transduction cascades composed of alternative pathways. A quantitative assessment of relative contributions of alternative pathways to one final cell signaling will help understand designing principles of the network. Unfortunately, a methodology for such assessment is still not available, partly because of lack of relatively mature mathematical models. On the other hand, in most biochemical cascades, existence of alternative pathways increases the complexity and thus the robustness of networks. The relationships between the topology and robustness of large-scale biochemical networks have been studied intensively recently. In small-scale networks, while feedback has been revealed as an important contributor for adaptation and robustness, the quantitative correlation between the topology/pathway redundancy of small networks and their robustness remains unknown. / In this thesis, apoptosis of bovine mammary gland epithelial cells was demonstrated to be induced when fibronectin, one of the major components of ECM, was degraded by overexpressed tPA via two potential ways: deprivation of attachment and the effects of fibronectin fragments. Secondly, a mathematical model for EGFR activation of the MAPK cascade, in which alternative pathways exist, was explored and it was found that the Shc-dependent pathway is both redundant and dominant. We hypothesize that the Shc-dependent pathway is important for EGFR to compete with other receptors, which need Shc to transduce cell signals; and this pathway is not aimed to increase the robustness of the EGFR cascade. Finally, for the general importance of alternative pathways to the network topology and robustness, several concepts have been proposed to decompose and quantitatively characterize the networks. We demonstrate that the pathnet score is a better assessment for robustness than the molecular connectivity.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85552 |
| Date | January 2004 |
| Creators | Gong, Yunchen, 1965- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Animal Science.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002210589, proquestno: AAINR12850, Theses scanned by UMI/ProQuest. |
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