Intracellular Scaffolds DVL and Parrestin

DVL has been mentioned previously several times as a central signaling relay for both P - catenin - dependent and - independent signaling. In addition to the physical interaction with FZDs through the highly conserved internal PDZ ligand domain KTxxxW [53] , DVL can interact with many proteins, such as axin, kinases, GTPases, guanine nucleotide exchange factors, and structural proteins [45, 54, 55], justifying the term signaling scaffold. DVL is composed of a DEP, a PDZ and a DIX domain: this molecular structure underlines DVL's versatility as a binding partner for many structurally unrelated proteins [45]. Regarding DVL localization in the cells, it has become clear that several distribution patterns are possible and that they are dynamically interchangeable depending on the degree of DVL expression, FZD expression, DVL kinase activity, and WNT stimulation (Fig. 5.3).

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Figure 5.3 Schematic view of the subcellular distribution of dishevelled (DVL). Exogenously expressed DVL in mammalian cells can be observed either evenly distributed throughout the cytosol or in DVL aggregates of various sizes. When coex-pressed with FZDs, DVL is recruited to the plasma membrane. In addition, nuclear DVL was reported to mediate WNT signaling. For details, see text.

Figure 5.3 Schematic view of the subcellular distribution of dishevelled (DVL). Exogenously expressed DVL in mammalian cells can be observed either evenly distributed throughout the cytosol or in DVL aggregates of various sizes. When coex-pressed with FZDs, DVL is recruited to the plasma membrane. In addition, nuclear DVL was reported to mediate WNT signaling. For details, see text.

In an excess of FZD, DVL is recruited to the receptor and shows a sub-membraneous distribution [56-58]. This pattern can also be achieved by WNT-overexpression in Drosophila or Xenopus [59, 60]. Exogenously overexpressed DVL commonly leads to a punctate pattern in the cytosol representing dynamic DVL-DVL aggregates of various sizes (e.g., References 30, 61, 62). However, this pattern has not clearly been established yet for endogenously expressed DVL proteins. DVL has also been observed as an evenly distributed cytosolic protein and a recent study [30] relating PS-DVL formation to DVL subcellular distribution showed that under conditions promoting PS-DVL (CK1e overexpression, WNT stimulation) DVL is predominantly evenly distributed, whereas with conditions promoting the unshifted/unphosphorylated form of DVL, the punctate distribution is preferred. The results suggest that DVL located in punctate represents the inactive form, while the evenly distributed DVL represent the active phosphorylated pool. Additionally, nuclear DVL regulating P-catenin-dependent responses, such as T cell factor (TCF)/lymphoid enhancer factor (LEF)-directed transcription and axis duplication in Xenopus embryos was observed under conditions where nuclear export is inhibited [63].

Another scaffolding protein that recently caught attention in the field is P-arrestin, which was originally described as a mediator of receptor desen-sitization for agonist-bound GPCRs and a signaling scaffold in G protein-

independent pathways [64] - Initial reports showed that P-arrestin1 promotes P - catenin - dependent transcriptional activity [65] . Further, P - arrestin is crucial for WNT-5A-induced FZD4 internalization [66]- However, in contrast to the classical GPCR/P - arrestin model (where P-arrestin interacts with the agonist-bound and phosphorylated receptor), P - arrestin prefers FZD4- bound DVL and mediates clathrin - dependent endocytosis of the receptor - 66] - Thus, P-arrestin interaction with DVL could serve as a negative desensitizing signal, as positive signal-promoting mechanisms, and/or as a means of determining signal specification. Further studies illustrated that P - arrestin interacts and colocalizes with DVL, and that this interaction is a necessary component for WNT-induced P-catenin signaling in vitro and in vivo [44]. Furthermore, Han and Kim described the importance of P - arrestin for convergent extension (CE) movements in Xenopus- implicating a crucial role for the activation of small RH0--ike GTPases [67] and that P-arrestin and CK1/2 define distinct branches of P - catenin - independent WNT signaling [68] .

The interaction between DVL and P-arrestin has the potential to serve as a pathway specification scaffold, acting as a WNT/FZD signaling platform [69]. Still, it is unclear if P-arrestin, in the context of WNT signaling, is (1) capable of recruiting signaling modules such as other kinases, phosphodiesterases, and E3 ligases [ 64] to promote cross- t alk with other pathways; (2) affects FZD desensitization; or (3) alters G protein coupling.

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