Defining mechanisms by which Axin and APC regulate Wnt signaling (2015)

Undergraduates: Natalie Deuitch, Mira Pronobis

Faculty Advisor: Mark Peifer
Department: Biology

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The Wnt signaling pathway controls cell fate and cell proliferation through down-regulation of the transcriptional co-activator ¿¿-catenin (¿¿cat) by a protein complex called the destruction complex (DC). Mutations in one component of the DC, tumor suppressor APC, account for over 80% of sporadic colon cancer cases leading to formation of colon polyps. APC functions together with the scaffold protein Axin and two kinases. Interestingly, both DC components share redundant regions such as ¿¿cat binding sites and domains that allow for self-polymerization, but it is unclear how APC and Axin use these regions to work together in ¿¿cat destruction.
We were able to define the essential regions in APC and in Axin needed for ¿¿cat degradation. To study how these regions work together we created constructs of APC and Axin that maintain just the essential regions and tested them for ability to target ¿¿cat. We also created a chimeric APC-Axin protein that links these essential regions of APC and Axin. We found that the chimera is able to reduce ¿¿cat levels and well at Wt APC and Axin when co-expressed. We also found that a small fragment of Axin associates along microtubules and were able to map it to a highly conserved motif in Axin proteins. We hypothesize that Axin-microtubule association plays a role in the recruitment of the DC from the cytoplasm to the plasma membrane when Wnt signaling is activated.