A tale of two circuits

This is a story about a fortunate coincidence.  In two papers published simultaneously last year, the Kirschner lab and the Alon lab each noticed that the signaling pathway they were studying appeared to have peculiar responses.  In both cases, the amount of output — or at least, what had previously been assumed to be the output — triggered by a given amount of signal was highly variable.  Something was clearly wrong with our assumptions.

The Kirschner lab’s pathway was the Wnt pathway, an extremely important pathway in both development and cancer.  The output of this pathway is a change in β-catenin levels.  But both modeling and experiment showed that β-catenin levels varied wildly.  There was little relationship between the amount of Wnt stimulation and the resulting absolute level of β-catenin.  Instead, the measurement that looked as if it behaved more reasonably was the ratio between the resting level of β-catenin and its level after stimulation, or the “fold change” after stimulation.  (Goentoro L & Kirschner MW 2009 Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling. Mol Cell. 36 872-84. PMID: 20005849).

Now, this is very odd.  We generally don’t think of cells as being able to remember the past (though the Silver lab is working on changing this).  So if the output of an important pathway is a ratio between the current level of a protein and an earlier level, we have two problems: how does the cell create this ratio? And once the ratio has been created, how does the cell read it?