Of Wingless Flies and Cancer
By: Carol A. Rouzer, VICB Communications
Published: May 26, 2010
VICB investigators dissect the regulation of a critical cancer signaling pathway.
The association between wingless fruit flies and cancer may not be obvious, but studies of both have led to the discovery of an important signaling pathway that controls development in the embryo and supports cell division and differentiation in the adult. Those original studies revealed that mutation of a particular gene in the fruit fly, Drosophila melanogaster, led to abnormal wing development. The same gene was found to be close to the integration point of a virus that causes mammary cancer in mice. A combination of “Wingless” and “integration” provided the odd name, Wnt (pronounced ‘wint’), for the protein coded by this gene which is highly conserved across all species that have bilateral symmetry.
Figure 1. (Above The fruit fly, Drosophila melanogaster has been used in genetic studies to dissect developmental pathways, including the Wnt signaling pathway. (Above-Right) Mammogram images showing normal breast tissue on the left and a breast cancer on the right. Abnormal Wnt signaling has been observed in many malignancies including breast cancer. (Image courtesy of Wikimedia Commons under the GNU Free Documentation License.)
We now know that Wnt signaling regulates the level of a second protein, β-catenin, which controls the transcription of a large number of genes, many of which are important in the modulation of cellular growth, differentiation, and interactions with neighboring cells. In the cytosol, β-catenin is bound to a “destruction complex” with three other proteins, an association that ultimately leads to its degradation (Figure 2). Wnt binding to specific cell surface receptors prevents β-catenin degradation, allowing the protein to accumulate, travel to the nucleus, and bind to its target genes. Although much is known about the composition and function of the destruction complex, the way that Wnt signaling prevents β-catenin degradation is still unclear. Now VICB investigator Ethan Lee and his colleagues [Jernigan, Cselenyi, et al. (2010) Science Signal., 3, ra37] provide exciting new insight into this important question.
Figure 2. The β-catenin destruction complex includes the proteins β-catenin, a x i n , A P C ( a d e n o m a t o u s polyposis coli), and GSK3 ( g l y c o g e n syntase kinase-3). GSK3 transfers a phosphate group (P) f r o m a d e n o s i n e triphosphate (ATP) to β-cateinin. The phosphate group causes β-catenin to dissociate from the complex, and it is subsequently degraded by the proteasome.
Key to the Lee lab’s findings is the class of Gproteins which play a role in transmitting the signal from a cell surface receptor to “effector proteins” responsible for executing the signal. The cell surface receptor complex for Wnt is comprised of two proteins, Frizzled (also named for a fruit fly mutation) and LRP6 (which stands for low density lipoprotein receptor-related protein 6). Because the structure of Frizzled indicates that it should transmit its signal via a G-protein, and because other G-protein-coupled receptors activate β-catenin signaling, the Lee lab investigated the effects of these proteins on the Wnt pathway. They found that, in fact, G-proteins help to promote Wnt signaling by stabilizing β-catenin levels and increasing β-catenin-mediated gene transcription.
Figure 3. Simplified model of how the Gβγ subunit of G-proteins may promote Wnt signaling. Activation of Frizzled by Wnt binding leads, in turn, to activation of the Gprotein and binding of the Gβγ subunit at the cell membrane. In turn, Gβγ binds GSK3, recruiting it to the receptor complex and removing it from the destruction complex. GSK3 transfers phosphate groups to LRP6, which, along with Wnt binding promotes its activity
To better understand the effect of G-proteins on Wnt signaling, the Lee lab focused on the role of the protein GSK3 (glycogen synthase kinase-3). GSK3 is a component of the destruction complex that promotes β-catenin degradation. The investigators found that a Gprotein subunit called Gβγ binds to GSK3, promoting its translocation to the cell membrane where it helps to activate LRP6. Thus, Gβγ appears to promote Wnt signaling in two ways - by disrupting GSK3’s function in the destruction complex and by using it to promote the activity of the Wnt receptor complex. Further studies suggest additional ways that G-proteins facilitate Wnt signaling in this complicated, multi-faceted pathway. The Lee lab’s findings are critical to understanding the function of the Wnt pathway. They help to explain how activation of other, seemingly unrelated receptors that act through G-proteins can affect Wnt signaling. The fact that aberrations in multiple components of the Wnt pathway, (including the destruction complex proteins APC and axin, in addition to β-catenin and Wnt itself) are associated with multiple types of cancer emphasizes the importance of this pathway to human health. Consequently, the Lee lab is seeking ways to use its knowledge of Wnt signaling to develop new chemotherapeutic agents for cancers that depend on aberrations in this important pathway.