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

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.Author summary: Tissues and organs are generally polarized along two axes. In addition to apical-basal epithelial polarity, tissues have often polarized cells or groups fo cells within the plane of the tissue, the so-called Planar Cell Polarity or PCP for short. PCP depends upon a conserved set of so-called core factors, which are conserved across the animal kingdom. The orientation of these factors and hence the cellular polarity also depends on the secreted Wnt-ligands. The key transmembrane core PCP factors, and thus main actors in the context are Frizzled (Fz) and Van Gogh (Vang/Vangl). We have identified a specific post-tranlational modification, a tyrosine phosphorylation of Vang/Vangl, which regulates the signaling outcome by directing with which cytoplasmic PCP factor Vang/Vangl will physically associate. Hence this phosphorylation event can be called a “phosphorylation switch”, which guides the transition of intermediary complex formation of Vang and Fz complexes, to the stable, polarized complexes anchored in this case by Vang/Vangl proteins. Interestingly, the formation of the unstable, intermediary complexes is equally important to the polarization process as is the final stable complex establishment.