A Van Gogh/Vangl tyrosine phosphorylation switch regulates its interaction with core Planar Cell Polarity factors Prickle and Dishevelled

Abstract

Epithelial tissues can be polarized along two axes: in addition to apical-basal polarity they are often also polarized within the plane of the epithelium, known as planar cell polarity (PCP). PCP depends upon the conserved Wnt/Frizzled (Fz) signaling factors, including Fz itself and Van Gogh (Vang/Vangl in mammals). Here, taking advantage of the complementary features of Drosophila wing and mouse skin PCP establishment, we dissect how Vang/Vangl phosphorylation on a specific conserved tyrosine residue affects its interaction with two cytoplasmic core PCP factors, Dishevelled (Dsh/Dvl1-3 in mammals) and Prickle (Pk/Pk1-3). We demonstrate that Pk and Dsh/Dvl bind to Vang/Vangl in an overlapping region centered around this tyrosine. Strikingly, Vang/Vangl phosphorylation promotes its binding to Prickle, a key effector of the Vang/Vangl complex, and inhibits its interaction with Dishevelled. Thus phosphorylation of this tyrosine appears to promote the formation of the mature Vang/Vangl-Pk complex during PCP establishment and conversely it inhibits the Vang interaction with the antagonistic effector Dishevelled. Intriguingly, the phosphorylation state of this tyrosine might thus serve as a switch between transient interactions with Dishevelled and stable formation of Vang-Pk complexes during PCP establishment.

Prickle and Ror modulate Dishevelled-Vangl interaction to regulate non-canonical Wnt signaling during convergent extension

“…There are at least three possibilities accounting for how Pk can assist Vangl2 to sequester Dvl. First, given that Dvl, Pk and Vang/Vangl can mutually interact with each other (Bastock et al, 2003; Humphries et al, 2023; Jenny et al, 2003; Takeuchi et al, 2003; Tree et al, 2002), Pk may stabilize a ternary Dvl/Pk/Vangl complex by simultaneously interacting with both Vangl and Dvl (Fig. 9a).…”

“…We, however, do not favor this possibility because 1) the binding between Pk and Dvl was reported to be quite weak (Bastock et al, 2003); 2) our unpublished data show that ΔPL, a Pk mutant lacking the PET/LIM domains necessary for Dvl binding (Takeuchi et al, 2003), can largely mimic wild-type Pk function. Furthermore, a new study in flies showed that the phosphorylation status of a conserved tyrosine in the cytoplasmic tail of Vang provides opposite binding preference for Pk and Dsh, suggesting that simultaneous binding of both Pk and Dsh to the C-terminus of Vang may not be possible (Humphries et al, 2023).…”

“…While our current study provides no evidence to support that Pk modulates Vangl N-terminal phosphorylation to regulate Vangl-Dvl interaction, this possibility remains an interesting idea and should be tested in the future using the reported phosphomutant and phosphomimetic Vangl2 (Yang et al, 2017). Finally, phosphorylation of a conserved C-terminal tyrosine residue of Vang was recently reported to decrease its binding with Dsh (Humphries et al, 2023), and could therefore provide a mechanism to control Vangl-Dvl interaction. But the regulatory mechanism of this tyrosine phosphorylation is not clear and does not seem to depend on Fz.…”

“…Our above model seemingly contradicts with the fly studies showing that Vang/Pk clusters are partitioned to the opposite cell cortexes from Fz/Dsh clusters and are clearly devoid of Dsh. These segregated clusters, however, seem to form progressively from initial symmetrically distributed PCP proteins along cell-cell junctions at early stages where Vang does co-localize with Dsh (Bastock et al, 2003), and a new study further implicated the functional importance of Vang-Dsh binding in fly PCP establishment (Humphries et al, 2023). Persistent contact and stable junctions between neighboring cells may facilitate feedback interaction to partition Vang/Pk from Dsh/Fz (Stahley et al, 2021).…”