Academic journal article Genetics

Testing Models of the APC Tumor Suppressor/[Beta]-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling

Academic journal article Genetics

Testing Models of the APC Tumor Suppressor/[Beta]-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling

Article excerpt

THE Wnt signaling pathway represents one of six evolu- tionary conserved pathways that collectively regulate animal development, yet are frequently misregulated in human disease (Clevers and Nusse 2012). During devel- opment, Wnt signaling regulates cell fate decisions that influence a myriad of developmental events as diverse as establishment of the vertebrate axis, control of bone develop- ment, and the wiring of the neural circuitry (Cadigan and Peifer 2009; Regard et al. 2012; Salinas 2012; Hikasa and Sokol 2013). Wnt signaling continues to be critical in adult homeostasis, as it is involved in the maintenance of certain mammalian stem cells (Holland et al. 2013). While Wnt sig- naling is clearly essential for an array of developmental events, misregulation of the pathway is the initiating event in the vast majority of colorectal cases. Truncating mutations in the negative regulator of Wnt signaling, adenomatous pol- yposis coli (APC), are responsible for both the hereditary co- lorectal cancer syndrome familial adenomatous polyposis (FAP) and .80% of spontaneous colon cancer cases (Polakis 2012).

APC functions as a gatekeeper of the intestinal epithelium by mediating proteolytic degradation of the Wnt signaling effector b-catenin (bcat). At the molecular level, APC nega- tively regulates bcat by participating in a multiprotein "de- struction complex" that consists of the core members Axin and the serine/threonine kinases glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1) (Stamos and Weis 2013). Once assembled into the destruction complex, bcat is sequentially phosphorylated by CK1 and GSK3, recognized by the SCFbTrCP E3 ubiquitin ligase, polyubiquitinated, and destroyed in the 26S proteasome. Thus in cells with an active destruction complex, bcat levels are low and Wnt target genes suppressed.

In cells receiving Wnt signal, the Wnt ligand binds to a coreceptor complex consisting of the seven-pass trans- membrane protein frizzled (Fz) and the single-pass mem- brane protein LRP5/6 (MacDonald and He 2012). Wnt binding to the receptor complex results in phosphorylation of the cytoplasmic tail of LRP5/6, which recruits Axin to the membrane. Membrane recruitment of Axin inactivates the destruction complex through a mechanism involving Dishev- eled (Dvl) (Bilic et al. 2007). He and colleagues suggest that Wnt signaling promotes an intramolecular conformational change in Axin that prevents assembly of bcat into the com- plex (Kim et al. 2013), whereas Clevers and colleagues pro- pose that Wnt signaling prevents recruitment of the E3 ligase to an intact destruction complex (Li et al. 2012). In either case, bcat remains hypophosphorylated and escapes ubiquitination, and its intracellular protein levels rise. bcat then translocates to the nucleus and associates with TCF/ LEF proteins at Wnt-responsive elements (WREs) and dis- places the Groucho repressor, thereby converting TCF/LEF from transcriptional repressors to activators. Ultimately these events result in expression of Wnt target genes such as c-myc and cyclin D1.

While substantial experimental evidence supports this general model of Wnt signal transduction, several funda- mental questions remain. One question is, What mechanistic role does APC play in the destruction complex? APC is a large protein with several putative protein - protein inter- action domains; therefore, APC was initially thought to be the scaffold for the complex. However, Axin was subse- quently identified as a negative regulator of Wnt signaling that binds all core components of the destruction complex (bcat, GSK3, CK1, APC, and Dvl), and other less well- characterized players such as the catalytic subunit of protein phosphatase 2A (PP2A) (Zeng et al. 1997; Sakanaka et al. 1998; Fagotto et al. 1999; Hsu et al. 1999). In addition, Axin can enhance the rate of bcat phosphorylation by CK1/GSK3, consistent with a scaffolding effect, whereas APC does not (Ha et al. 2004). These findings make Axin a stronger can- didate to be the scaffold, leaving the mechanistic role of APC in the destruction complex mysterious. …

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