Figure 3. Multiple feedback loops connect the ERK and Wnt signaling pathways.

(A) The ERK and Wnt signaling pathways are highly interconnected with each other through multiple feedback loops. Red lines with a bar-end denote negative feedback links, while blue lines with an arrow-end denote positive feedback links. The feedback link F₁ represents Ras stabilization by the β-catenin/TCF complex, F₂ represents the inhibition of MEK by RKIP, F₃ represents the inhibition of SOS/Grb2 complex by ERK, F₄ represents the inhibition of GSK3β by ERK, F₅ represents the inhibition of PKCδ by GSK3β, and F₆ represents the expression of Axin by β-catenin/TCF complex. (B) Principal component analysis (PCA) of the network topologies that are determined by different feedback combinations. The 32 network topologies were analyzed using PCA with respect to the five outputs: the activation of ERK, the expression of Snail, Slug and E-cadherin, and the formation of the β-catenin/TCF complex, and then the results were projected onto two dimensions for which 96% of output variances were accounted. Label of each feedback combination is shown in the right of this panel.