Molecular mechanisms mediating asymmetric subcellular localisation of the core planar polarity pathway proteins

Abstract

Planar polarity refers to cellular polarity in an orthogonal plane to apicobasal polarity, and is seen across scales from molecular distributions of proteins to tissue patterning. In many contexts it is regulated by the evolutionarily conserved ‘core' planar polarity pathway that is essential for normal organismal development. Core planar polarity pathway components form asymmetric intercellular complexes that communicate polarity between neighbouring cells and direct polarised cell behaviours and the formation of polarised structures. The core planar polarity pathway consists of six structurally different proteins. In the fruitfly Drosophila melanogaster, where the pathway is best characterised, an intercellular homodimer of the seven-pass transmembrane protein Flamingo interacts on one side of the cell junction with the seven-pass transmembrane protein Frizzled, and on the other side with the four-pass transmembrane protein Strabismus. The cytoplasmic proteins Diego and Dishevelled are co-localised with Frizzled, and Prickle co-localises with Strabismus. Between these six components there are myriad possible molecular interactions, which could stabilise or destabilise the intercellular complexes and lead to their sorting into polarised distributions within cells. Post-translational modifications are key regulators of molecular interactions between proteins. Several post-translational modifications of core proteins have been reported to be of functional significance, in particular phosphorylation and ubiquitination. In this review, we discuss the molecular control of planar polarity and the molecular ecology of the core planar polarity intercellular complexes. Furthermore, we highlight the importance of understanding the spatial control of post-translational modifications in the establishment of planar polarity.

Celsr1 adhesive interactions mediate the asymmetric organization of planar polarity complexes

“…Transmembrane proteins Frizzled (Fz) and Van Gogh-like (Vangl) localize to opposing sides of the junction, where they interact intercellularly in complex with atypical cadherin Celsr1. Cytoplasmic proteins Dishevelled and Prickle colocalize with Fz and Vangl, respectively, and are important for amplifying asymmetry through oligomerization domains that mediate self-recruitment, and by promoting mobility and disassembly of the oppositely oriented complex ( Devenport, 2014 ; Butler and Wallingford, 2017 ; Harrison et al, 2020 ). How Celsr1-mediated intercellular interactions contribute to this asymmetric reorganization of PCP protein complexes is poorly understood.…”

The Emerging Mechanisms of Wnt Secretion and Signaling in Development

“…Initially identified in Drosophila, the PCP pathway consists of six core components; Fz, Dsh, Prickle (Pk), Strabismus/Van Gogh (Vang) or Vang-like (Vangl) in vertebrates, Flamingo (Fmi) and Diego (Dgo), which are conserved amongst the metazoans (Eaton, 1997;Seifert and Mlodzik, 2007;Hale and Strutt, 2015;Butler and Wallingford, 2017;Humphries and Mlodzik, 2018). In various tissues, the pathway is governed by asymmetric localization of the core components as two separate complexes consisting of Vang-Fmi-Pk and Fz-Fmi-Dsh-Dgo (Usui et al, 1999;Axelrod, 2001;Feiguin et al, 2001;Shimada et al, 2001;Strutt, 2001;Tree et al, 2002;Bastock et al, 2003), at the opposite ends of the cell (reviewed in Harrison et al, 2020). These complexes activate downstream signaling which determines various polarized cellular outputs such as cell shape regulation, the orientation of primary cilia in the vertebrate inner ear, directed cell migration and the directional organization of tissues (Yang and Mlodzik, 2015;Humphries and Mlodzik, 2018).…”

Decoding Dishevelled-Mediated Wnt Signaling in Vertebrate Early Development

“…Detailed analysis of other conserved domains or isoform-specific regions, such as the basic region preceding the PDZ domain, the proline-rich region and histidinesingle amino acid repeats in the C-terminal region beyond the DEP domain, and the extreme C-terminus, may provide insights into Dvl-mediated signal transduction. Because Dvl post-translational modifications, in particular phosphorylation and ubiquitination, and Dvl interaction partners are important for subcellular localizations and specific functions of Dvl proteins (Sharma et al, 2018;Harrison et al, 2020), it is of interest to understand how these modulate Dvl activity and dictate signaling outcomes in key developmental processes. Indeed, dysregulation of Dvl phosphorylation impairs both Wnt/ßcatenin and Wnt/PCP signaling during zebrafish and Xenopus embryogenesis (Shimizu et al, 2014;Rauschenberger et al, 2017).…”