ctional Roles of Multiple Feedback Loops in Extracellular al-Regulated Kinase and Wnt Signaling Pathways

nloaded helial-mesenchymal transition (EMT) is a key event in the generation of invasive tumor cells. A hallmark T is the repression of E-cadherin expression, which is regulated by various signal transduction pathways ing extracellular signal-regulated kinase (ERK) and Wnt. These pathways are highly interconnected via le coupled feedback loops (CFL). As the function of such coupled feedback regulations is difficult to e experimentally, we used a systems biology approach where computational models were designed to t biological effects that result from the complex interplay of CFLs. Using epidermal growth factor (EGF) nt as input and E-cadherin transcriptional regulation as output, we established an ordinary differential on model of the ERK and Wnt signaling network containing six feedback links and used extensive comsimulations to analyze the effects of these feedback links in isolation and different combinations. The show that the feedbacks can generate a rich dynamic behavior leading to various dose-response patnd have a decisive role in determining network responses to EGF and Wnt. In particular, we made two tant findings: first, that coupled positive feedback loops composed of phosphorylation of Raf kinase tor RKIP by ERK and transcriptional repression of RKIP by Snail have an essential role in causing a -like behavior of E-cadherin expression; and second, that RKIP expression inhibits EMT progression venting E-cadherin suppression. Taken together, our findings provide us with a system-level understandby pre ing of how RKIP can regulate EMT progression and may explain why RKIP is downregulated in so many metastatic cancer cells. Cancer Res; 70(17); 6715–24. ©2010 AACR.