PCatenin Dependent Signaling

WNTs were originally subdivided into WNT-1-like and WNT-5A-like groups on the basis of differential transforming potential in a mammary tumor cell line. WNT-1-like WNTs, such as WNT-3A, mediate P-catenin-dependent signaling. WNT-3A, one of the purified and commercially available WNTs, generally activates P-catenin signaling in various mammalian cell types. In Xenopus models, P-catenin signaling can be studied by the anterior-posterior axis duplication assay [42]. On the molecular level, WNTs interact with both FZDs and their co-receptors low-density lipoprotein receptor-related protein (LRP5/6) to promote signaling that results in inhibition of a constitutively active destruction complex, which by GSK3-dependent phosphorylation, primes P- catenin to degradation in the proteasome - 36] - The composition of the destruction complex is not yet completely understood, but the most important players are GSK3, axin, and APC (adenomatous polyposis coli). Upstream of this inhibition of the degradation complex, WNT-stimulation activates the central phos-phoprotein DVL, which is dependent on casein kinases [31, 43] and the scaffold protein P-arrestin [44]. DVL activity is regulated by phosphorylation, subcel-lular localization, and degradation, and DVL is a central relay station of many—if not all—WNT/FZD signaling pathways [45]. DVL activation status can be monitored by an electrophoretic mobility shift, which is dependent on DVL phosphorylation. The shifted band on an immunoblot is therefore often referred to as phosphorylated and shifted DVL (PS-DVL; [31, 46]). The inhibition of the degradation complex is apparently accomplished through a collaborative communication through WNT-bound FZDs and LRPs - 47] -Interestingly, there is evidence that WNT-3A--nduced P-catenin signaling is composed of a rapid, low- dose and a slower, high- dose pathway, mediated through cooperation between LRPs and FZDs [ 31] where the rapid, LRP-dependent pathway is independent of PS-DVL formation.

Even though this WNT signaling route is being characterized in ever greater detail, important gaps need to be filled. For example, it is still unclear how the WNT--nduced FZD/LRP complex communicates, or when it is required; which LRP kinases other than GSK3 are involved and how they are recruited [47, 48]. Moreover, the regulatory role of DVL for LRP phosphorylation and the inhibition of GSK3 still remain obscure.

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