Systematic Analysis of Crosstalk in the PDGF Receptor Signal Transduction Network

Intracellular signal transduction is traditionally characterized in terms of pathways, comprised of serial activation processes. Although it is appreciated that canonical signaling pathways are simply dominant routes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway crosstalk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated crosstalk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from crosstalk, PI3K enhances Erk activation in multiple ways. Whereas simultaneously blocking Ras and PI3K abolishes PDGF-stimulated Erk phosphorylation, each pathway makes an independent contribution to Erk activation, and PI3K affects Ras activation as well. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.

Author dc:creator

• Wang, Chun-Chao

Advisors dc:contributor.advisor

• Carla Mattos, Committee Member
• Jason M. Haugh, Committee Chair
• Robert M. Kelly, Committee Member
• Balaji Rao, Committee Member

• signal transduction network
• PI3K
• Akt
• Ras
• Raf
• kinetic model
• PDGF
• negative feedback loop
• crosstalk
• Erk

Statement dc:rights

• I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dis sertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.

Dc Identifier Other

etd-08072008-162743

OAI record oai:identifier

https://repository.lib.ncsu.edu/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arepository.lib.ncsu.edu%3A1840.16%2F3901