Crosstalk Between Phosphoinositide 3-Kinase and Extracellular Signal-regulated Kinase Pathways in Platelet-derived Growth Factor Receptor-mediated Signaling

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Title: Crosstalk Between Phosphoinositide 3-Kinase and Extracellular Signal-regulated Kinase Pathways in Platelet-derived Growth Factor Receptor-mediated Signaling
Author: Wang, Chun-Chao
Advisors: David F. Ollis, Committee Member
Robert M. Kelly, Committee Member
Jason M. Haugh, Committee Chair
Abstract: Cells control their behavior by maintaining a balance between signal transduction pathways. The disruption of this balance has been implicated in the evolution of normal cells into cancer cells. People expected to inhibit or activate a specific pathway to achieve the cure of cancer. However, signaling pathways are usually woven together through so-called cross-talk interaction and it is almost impossible to design a drug specifically targeting a pathway. Thus, the fundamental understanding of the intracellular signaling processes is important on medicine and biotechnology. Platelet-derived growth factor (PDGF) is a potent stimulator of cell growth and motility. PDGF-induced phosphoinositide 3-kinase (PI 3-kinase)/Akt and Ras/extracellular signal-regulated kinase (Erk) pathways are thought to play central roles in the regulation of cell survival and proliferation. Crosstalk between PI 3-kinase/Akt and Ras/Erk pathways has provided important hints for how PDGF receptor activation may control cellular function. The apparently contradictory findings among recently studies suggest that the cross-talk mechanisms are not fully understood. In this study, we aim to systematically analyze this signaling network, comprised of Ras/Erk and PI 3-kinase/Akt pathways, stimulated by PDGF. Molecular level control over the signaling network, through genetic and pharmacological intervention, will allow these complex regulatory interaction to be isolated. We assessed the phosphorylation of Akt and Erk as the outputs of PI 3-kinase/Akt and Ras/Erk pathways respectively, and detected DNA synthesis and cell numbers to analyze the effect of these two pathways on the resulting life and death decisions. Accumulating evidence has demonstrated that differences in the strength of stimulus, and the duration and magnitude of activity of signal molecules, determine signaling specificity. We offer a quantitative approach — crosstalk titration — to analyze the effect of our intervention strategies on the signaling network. Our results demonstrated that Ras signals are required for full activation of PI 3-kinase/Akt, consistent with the idea that the PDGF receptors and Ras-GTP modulate PI 3-kinase activity in a cooperative fashion. The relevance of PI 3-kinase for Erk activation is complicated. We observed that PI 3-kinase may play multiple role in regulation of the Erk pathway, both positive and negative, dependent on the magnitude of PDGF and the strength and duration of signaling molecular. The extent to which PI 3-kinase activity influences Ras/Erk signaling is still uncertain. Additionally, we found that PDGF-induced DNA synthesis involved the functions of Ras, PI 3-kinase, and MEK. The relevance of Akt on PDGF-induced DNA synthesis is not fully understood, leading the questions open for further investigation.
Date: 2005-11-25
Degree: MS
Discipline: Chemical Engineering

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