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.

Introduction

Many cells require asymmetrical architecture — termed polarity — that allows structures to be compartmentalised within a cell in order to fulfil their function. Apicobasal polarity is common in many cell types such as neurons, where it enables unidirectional signal transduction, and epithelial cells, enabling unidirectional secretion. Cells can also be polarised in an orthogonal plane, which is termed planar polarity, also known as planar cell polarity (PCP). Planar polarity allows the placement of structures to be co-ordinated with the tissue axis and with neighbouring cells. Planar polarity is evolutionarily conserved [1] and has been reported in a range of tissues in both vertebrates and invertebrates, and is vital to proper tissue development and function. Examples of planar polarity enabled processes include cilia mediated convection currents in the oviduct, the arrangement of hair cells in the inner ear, and the overlapping nature of mammalian fur (reviewed in [2–4]). Planar polarity has been reported from as early as epiblast formation in zebrafish [5] and primitive endoderm formation in mouse [6]. Its loss is implicated in neural tube closure defects [7], spermatogenesis defects [8], deafness [9], and heart defects [10]. As such the underlying mechanisms are of broad interest.

At a molecular level, planar polarity principally involves the formation of intercellular complexes with heterologous components. Planar polarity can be genetically regulated by two well-characterised pathways: the Fat-Dachsous (Ft-Ds) pathway and the core planar polarity pathway (‘core pathway', see Table 1). In the Ft-Ds pathway, the atypical cadherins Ft and Ds localise to opposite cell ends [11–13], where they interact intercellularly to form a heterophilic complex [14,15]. The Drosophila core pathway protein distribution consists of an intercellular homodimer of the atypical cadherin Flamingo (Fmi; also known as Starry Night [Stan]) [16] and asymmetric localisation of associated proteins (summarised in Figure 1A,C). The seven-pass transmembrane protein Frizzled (Fz) and the cytoplasmic proteins Dishevelled (Dsh) and Diego (Dgo) are found on one side of the Fmi homodimer [17–21], and on the other side are the four-pass transmembrane protein Strabismus (Stbm, also known as Van Gogh [Vang]) and the cytoplasmic protein Prickle (Pk) [22,23].

Principles of planar cell polarity.

Figure 1.
Principles of planar cell polarity.

(A) Schematic of localisation of core planar polarity pathway protein complexes in cells of the Drosophila pupal wing. Proximal localisation of Stbm (orange) and distal localisation of Fz (green) at apicolateral cell junctions leads to trichome (grey) emergence from distal cell edges. (B and C) Evolution of symmetry breaking cluster formation. (B) Fmi homodimers are stabilised by Fz localisation on one side of the complex at junctions between neighbouring cells. (C) Stbm localises to the apposing cell edge and the cytoplasmic proteins Pk, Dsh and Dgo localise proximally and distally in the complex as shown. (D) Image of dorsal surface of a wild-type Drosophila wing, showing uniform distal orientation of trichomes. Proximal is left, and anterior is up. (E) Image of dorsal surface of wing from a pkpk-sple13 mutant fly, showing a swirled trichome pattern. (F) Confocal microscope image of Drosophila pupal wing epithelium, immunolabelled for Fmi (green, localised preferentially to proximodistal cell boundaries) and showing actin-rich trichomes (red, emerging from distal cell edges). (G and H) Confocal microscope image of a Drosophila pupal wing epithelium genetically mosaic for dshV26 mutant tissue, marked by loss of blue β-gal immunolabelling and outlined in white (G). Fmi (green) and Stbm (red, or white in H) are asymmetrically localised at proximodistal cell boundaries at the apicolateral cell junctions (left and right cell edges) in wild-type tissue, but lose this asymmetric localisation in mutant tissue. This shows that Dsh activity is required for planar polarisation of core pathway components such as Fmi and Stbm. (IK) Molecularly asymmetric complexes (I) are sorted by feedback interactions (J) so that they all align in the same orientation (K). Complexes of opposite orientation are destabilised (red inhibitory symbols) and complexes of the same orientation are stabilised (black arrows).

Figure 1.
Principles of planar cell polarity.

(A) Schematic of localisation of core planar polarity pathway protein complexes in cells of the Drosophila pupal wing. Proximal localisation of Stbm (orange) and distal localisation of Fz (green) at apicolateral cell junctions leads to trichome (grey) emergence from distal cell edges. (B and C) Evolution of symmetry breaking cluster formation. (B) Fmi homodimers are stabilised by Fz localisation on one side of the complex at junctions between neighbouring cells. (C) Stbm localises to the apposing cell edge and the cytoplasmic proteins Pk, Dsh and Dgo localise proximally and distally in the complex as shown. (D) Image of dorsal surface of a wild-type Drosophila wing, showing uniform distal orientation of trichomes. Proximal is left, and anterior is up. (E) Image of dorsal surface of wing from a pkpk-sple13 mutant fly, showing a swirled trichome pattern. (F) Confocal microscope image of Drosophila pupal wing epithelium, immunolabelled for Fmi (green, localised preferentially to proximodistal cell boundaries) and showing actin-rich trichomes (red, emerging from distal cell edges). (G and H) Confocal microscope image of a Drosophila pupal wing epithelium genetically mosaic for dshV26 mutant tissue, marked by loss of blue β-gal immunolabelling and outlined in white (G). Fmi (green) and Stbm (red, or white in H) are asymmetrically localised at proximodistal cell boundaries at the apicolateral cell junctions (left and right cell edges) in wild-type tissue, but lose this asymmetric localisation in mutant tissue. This shows that Dsh activity is required for planar polarisation of core pathway components such as Fmi and Stbm. (IK) Molecularly asymmetric complexes (I) are sorted by feedback interactions (J) so that they all align in the same orientation (K). Complexes of opposite orientation are destabilised (red inhibitory symbols) and complexes of the same orientation are stabilised (black arrows).

Table 1
Planar polarity proteins in flies and vertebrates
Drosophila proteinSymbolVertebrate homologues
Ft-Ds pathway 
Fat Ft Fat 
Dachsous Ds Dchs 
Four-jointed Fj Fjx1 
Core pathway 
Flamingo/Starry Night Fmi/Stan Celsr 
Frizzled Fz Fz/Fzd 
Strabismus/Van Gogh Stbm/Vang Vangl 
Prickle Pk Pk 
Dishevelled Dsh Dvl 
Diego Dgo Diversin 
Drosophila proteinSymbolVertebrate homologues
Ft-Ds pathway 
Fat Ft Fat 
Dachsous Ds Dchs 
Four-jointed Fj Fjx1 
Core pathway 
Flamingo/Starry Night Fmi/Stan Celsr 
Frizzled Fz Fz/Fzd 
Strabismus/Van Gogh Stbm/Vang Vangl 
Prickle Pk Pk 
Dishevelled Dsh Dvl 
Diego Dgo Diversin 

Due to simple husbandry, a small genome and fast reproductive cycle, the fruitfly Drosophila melanogaster has been at the forefront of genetic research for over a century. Readily accessible readouts of planar polarity in Drosophila include photoreceptor orientation within the eye (ommatidia), the organisation of surface bristles on the body, and wing hair (trichome) placement originating from distal cell edges (Figure 1A,D–F). Drosophila genetic tools allow for powerful and versatile experimental design. These include the rapid generation of transgenic animals, the ability to create mosaic mutants (Figure 1G,H) and the ability to express genes ectopically. These experimental paradigms have allowed for the robust assessment of the roles of particular gene products during development, including the elucidation of the genetic control of planar polarity. Here we primarily discuss mechanisms of planar polarity establishment in the developing Drosophila wing, which is a simple epithelial sheet, allowing easy imaging of fixed samples (Figure 1F–H), while also being accessible for live imaging.

Tissue level control of patterning in planar polarity

A pervading question within the planar polarity field regards the nature of a global cue to co-ordinate polarity with the tissue axis. Does it exist? And if so, what is it? Structures within epithelial sheets that are hundreds of cells wide are all co-ordinated to be planar polarised on parallel vectors. Global polarity of the Ft-Ds system appears to be based in part upon a vectoral gradient of Four-jointed (Fj) distribution, which is expressed in a graded fashion along the proximodistal axis of the developing wing [24,25]. Both Ft and Ds are phosphorylated by the kinase activity of Fj, with opposing effects on their heterophilic binding affinities. This results in phosphorylated Ft having an increased binding affinity for Ds, but phosphorylated Ds having a decreased affinity for binding Ft [26–28]. This leads to a local imbalance of Ft and Ds localisation within each cell, which in turn propagates to neighbouring cells. A 3% difference in Fj activity between neighbouring cells was found to be sufficient to generate Ft-Ds planar polarity in silico [28].

A global cue for the core pathway has been more elusive. Secreted Wnt ligands are known to bind to Fz receptors [29], and Wnts are expressed in gradients in the developing Drosophila wing [30–32]. Ectopic overexpression of Wnts can reorient trichomes in the wing [33]. However, an instructive role for Wnts in directing trichome orientation has been difficult to demonstrate using loss-of-function mutations (reviewed in [34]). In addition, it has been proposed that the Ft-Ds system acts upstream of the core pathway, either by a direct interaction between the two pathways or by biasing microtubule orientation and Fz/Dsh transport distally within the cell (reviewed in [34]). Nevertheless, the Ft-Ds system only influences trichome orientation over part of the wing, suggesting that other factors must also contribute to generating the global cue for the core pathway. These have been suggested to include growth, morphogenesis and mechanical tension [4,34,35].

Molecular interactions of the core planar polarity pathway proteins

During pupal wing development, core pathway proteins are asymmetrically localised at the apico-lateral membrane, at the adherens zone. This polarisation is evident to some degree throughout development, but becomes more pronounced prior to trichome formation in the wing [36,37]. The establishment of core pathway planar polarity requires a first symmetry breaking step: the decision for Fz to accumulate distally and Stbm proximally around Fmi:Fmi homodimers at proximodistal cell boundaries (Figure 1C). In fmi mutant flies there is a reduction in Stbm and Pk at cell boundaries [22,23] and a loss of Fz, Dsh, and Dgo [17–20]. In fz mutant flies, Fmi is also mostly lost from the proximodistal cell boundaries and is observed at the apical cell membrane, suggesting that Fz is needed to stabilise Fmi homodimers [38]. Furthermore, Fmi appears to preferentially homodimerise when Fz is on only one side of the complex, suggesting that a Fz-Fmi:Fmi bridge is the backbone of the core pathway (Figure 1B) [38,39]. The cytosolic proteins and Stbm are required for the sorting of these asymmetric molecular bridges to a uniform orientation on proximodistal cell edges [17–20,22,23].

Beyond evidence that there is some polarised transport of Fz and Dsh distally on microtubule arrays [40,41], cellular mechanisms that sort the core proteins across the cell are not known. However, it has been reported that the core pathway proteins can self-organise. At cell boundaries in mosaic analysis experiments, fz mutant cells preferentially recruit Fz from their neighbours, whilst in the mutant cell Stbm localises to membranes apposing the wild-type neighbours, leading to a reversal of polarity on the distal side of the mosaic tissue [20,23,42,43]. This de novo planar polarity axis can extend across several cells suggesting an intracellular signal propagates away from the boundary cue [44].

Individual molecular interactions have been observed between many of the core pathway proteins. At least in vitro Stbm, Pk, Dsh, and Dgo can all interact with one another, while there also is evidence that Fmi may interact directly with Fz or Stbm, and Fz may interact with Stbm and Dsh (Table 2) [21–23,43,45–55]. Broadly speaking, these interactions are thought to underlie self-organisation, where complexes of the same orientation are stabilised, and complexes of opposite organisation are destabilised (Figure 1I–K). Feedback mechanisms driven by selective stabilisation/destabilisation of intercellular complexes could serve to amplify any small polarity bias generated by a global cue, to generate robust polarity [56–59].

Table 2
Physical interactions between the core planar polarity proteins
Protein 1Protein 2MethodReferences
Fmi Fz co-immunoprecipitation [43
Celsr11 Vangl21 co-immunoprecipitation [52
Fzd31 Vangl21 co-immunoprecipitation [51
Fzd51 Dvl11 PEPSCAN-based ELISA [55
Stbm
Vangl21 
Stbm
Vangl11, Vangl21 
co-immunoprecipitation, GST pulldown, yeast two-hybrid [46,54
Stbm
Vangl12, Vangl22 
Pk
Pk12, Pk22 
co-immunoprecipitation, GST pulldown, mass spectrometry of immunoprecipitates [23,46,53
Stbm
Vangl3,4
Vangl11, Vangl21 
Dsh
Dvl3,4
Dvl11, Dvl21, Dvl31 
co-immunoprecipitation, GST pulldown, yeast two-hybrid [23,45,46,48
Stbm Dgo GST pulldown [21
Pk Pk GST pulldown [46
Pk
Pk3 
Dsh
Dvl3 
GST pulldown [22,47,49
Pk Dgo GST pulldown [21
Dsh
Dvl21 
Dgo
Diversin1 
co-immunoprecipitation, GST pulldown, yeast two-hybrid [49,50
Protein 1Protein 2MethodReferences
Fmi Fz co-immunoprecipitation [43
Celsr11 Vangl21 co-immunoprecipitation [52
Fzd31 Vangl21 co-immunoprecipitation [51
Fzd51 Dvl11 PEPSCAN-based ELISA [55
Stbm
Vangl21 
Stbm
Vangl11, Vangl21 
co-immunoprecipitation, GST pulldown, yeast two-hybrid [46,54
Stbm
Vangl12, Vangl22 
Pk
Pk12, Pk22 
co-immunoprecipitation, GST pulldown, mass spectrometry of immunoprecipitates [23,46,53
Stbm
Vangl3,4
Vangl11, Vangl21 
Dsh
Dvl3,4
Dvl11, Dvl21, Dvl31 
co-immunoprecipitation, GST pulldown, yeast two-hybrid [23,45,46,48
Stbm Dgo GST pulldown [21
Pk Pk GST pulldown [46
Pk
Pk3 
Dsh
Dvl3 
GST pulldown [22,47,49
Pk Dgo GST pulldown [21
Dsh
Dvl21 
Dgo
Diversin1 
co-immunoprecipitation, GST pulldown, yeast two-hybrid [49,50

See Table 1 for fly and vertebrate homologues. Interactions were between fly molecules unless otherwise stated.

1

Mouse;

2

human;

3

Xenopus;

4

zebrafish.

Some potential feedback mechanisms acting in core pathway self-organisation have been uncovered. Based on binding interactions, it was proposed that Dgo and Pk compete for binding to Dsh, with Dgo promoting Fz activity and Pk inhibiting it (Figure 2A) [22,49]. Consistent with this, more recent work has shown that Pk acts via Dsh to destabilise Fz in the same cell, and also acts to stabilise Fz via Stbm using trans-interactions in the neighbouring cell (Figure 2A,B) [60,61]. Furthermore, overexpression of Pk leads to the co-ordinated internalisation of Pk, Stbm and Fmi, and if Fz is forced to accumulate on particular cell boundaries in genetic mosaics, Pk promotes exclusion of Stbm from these cell boundaries (Figure 2C) [62]. In addition, Dsh binding to the Fz-Fmi:Fmi-Stbm complex results in the stabilisation of Pk in the adjacent cell [63]: if Dsh is acutely depleted in one cell, free Pk in the adjacent cell then destabilises Dsh-Fz in this cell, and thus leads to a propagating wave of core complex destabilisation (Figure 2D) [63].

Mechanisms of planar cell polarity establishment.

Figure 2.
Mechanisms of planar cell polarity establishment.

(AD) Putative stabilising and destabilising interactions between the core proteins on two neighbouring cell membranes (grey solid lines). Black arrows indicate stabilising interactions and red inhibitory symbols indicate destabilising interactions. Dotted grey arrows indicate removal of proteins from the intercellular complex. (A) Pk and Dgo compete for Dsh binding. Pk binding to Dsh leads to destabilisation of Fz. (B) Pk acts through Stbm to stabilise Fz in the adjacent cell. (C) Pk promotes Fmi and Stbm endocytosis in the presence of Fz on the same membrane. (D) Dsh stabilises Pk in the adjacent cell. (E,F) Post-translational modifications of the core proteins. Purple stars indicate ubiquitination of a core protein (E) and yellow stars indicate phosphorylation (F). Modifying enzymes acting in Drosophila are in grey and those only known to act in vertebrates are in blue. (G) Stoichiometry of core pathway complexes. A homodimer of Fmi associates with one Fz, two Dsh and one Dgo molecule on one side of the complex and with six Stbm and one Pk molecule on the other. (H) Clustering of intercellular complexes in parallel arrays results in multiple stabilising interactions, and complexes undergo a phase transition to form stable puncta. (I) Outside of puncta, core protein complexes are in both orientations, and destabilising feedback interactions prevent clustering of complexes, leading to complexes that are less densely packed.

Figure 2.
Mechanisms of planar cell polarity establishment.

(AD) Putative stabilising and destabilising interactions between the core proteins on two neighbouring cell membranes (grey solid lines). Black arrows indicate stabilising interactions and red inhibitory symbols indicate destabilising interactions. Dotted grey arrows indicate removal of proteins from the intercellular complex. (A) Pk and Dgo compete for Dsh binding. Pk binding to Dsh leads to destabilisation of Fz. (B) Pk acts through Stbm to stabilise Fz in the adjacent cell. (C) Pk promotes Fmi and Stbm endocytosis in the presence of Fz on the same membrane. (D) Dsh stabilises Pk in the adjacent cell. (E,F) Post-translational modifications of the core proteins. Purple stars indicate ubiquitination of a core protein (E) and yellow stars indicate phosphorylation (F). Modifying enzymes acting in Drosophila are in grey and those only known to act in vertebrates are in blue. (G) Stoichiometry of core pathway complexes. A homodimer of Fmi associates with one Fz, two Dsh and one Dgo molecule on one side of the complex and with six Stbm and one Pk molecule on the other. (H) Clustering of intercellular complexes in parallel arrays results in multiple stabilising interactions, and complexes undergo a phase transition to form stable puncta. (I) Outside of puncta, core protein complexes are in both orientations, and destabilising feedback interactions prevent clustering of complexes, leading to complexes that are less densely packed.

In the pupal wing, core pathway proteins are observed along the length of the proximodistal junctional membranes in uneven abundance, and these localised concentrations are termed ‘puncta’. Fluorescence recovery after photobleaching (FRAP) experiments on live in vivo wing junctions have shown that core proteins in these puncta are more stable than in the non-puncta regions [64,65]. The proteins within these puncta are also highly asymmetrically localised compared with neighbouring non-puncta regions [62,64]. These data support the idea of mutual exclusion of unsorted complexes: antiparallel complexes are excluded from uniformly oriented puncta, while sorted complexes are mutually stabilised (Figure 1J,K).

Strutt and Gamage [65] directly measured the stoichiometry of core pathway proteins in these puncta, by tagging each protein individually with EGFP and comparing intensity in live pupal wings. When compared with immunolabelled Fmi, signal intensity of all six core proteins increased linearly with puncta size. This supports the idea that all puncta have the same composition. The stoichiometry in puncta was determined to be two Fmi (trans-homodimer) with approximately two Dsh, one Fz, and one Dgo on the distal membrane, and six Stbm with one Pk on the proximal membrane of the adjoining cell (Figure 2G). Interestingly, this stoichiometry is consistent between stable puncta and unstable non-puncta regions within the same cell.

Notably, the stoichiometry of the cytoplasmic proteins in puncta is dependent on their expression levels [65]. For example, if Dsh was overexpressed, more was found within both stable puncta and unstable non-puncta regions. However, the other complex components maintained their normal ratios. Likewise, when Dsh levels were halved, the ratio within stable and unstable regions halved for only Dsh [65]. In contrast, halving the expression of Fmi resulted in a halving of Fz recruitment into puncta, maintaining the 2 : 1 ratio of Fmi:Fz and supporting the asymmetric molecular bridge hypothesis (Figure 1B). This suggests that the cytosolic proteins form a dosage-dependent ‘cloud' around a fixed Fz-Fmi:Fmi backbone. The conclusion of this work is that core protein complexes within both stable puncta and unstable non-puncta coalesce via multivalent protein–protein interactions between the different proteins. Overall, it was suggested that when locally ordered complexes reach a critical density they undergo a phase transition from an unstable, fluid state, to a more solid stable state in puncta (Figure 2H,I) [65].

The Ft and Ds proteins are also organised into puncta, with FRAP experiments showing a more stable population in puncta [28]. Analogous to the core pathway proteins, puncta formation is dependent on formation of intercellular heterodimers between Ft and Ds. Furthermore, puncta stability is dependent on trans-binding affinity [28].

Post-translational modifications influence protein–protein interactions and complex sorting

Post-translational modifications (PTMs) are ubiquitous in mediating feedback interactions in cell polarity, from symmetry breaking in yeast budding, to anteroposterior patterning of PAR proteins in C. elegans embryos and apicobasal polarity of epithelial cells [66–68]. The core pathway proteins have a complex network of PTMs that include ubiquitination and phosphorylation (Table 3). Ubiquitination of a protein can target it for proteasomal degradation, or can promote internalisation of transmembrane proteins that are then either recycled back to the plasma membrane or degraded in the lysosome [69]. Therefore, targeted ubiquitination of a core protein could promote destabilisation/removal of that protein from a complex and complex sorting. Phosphorylation can alter protein stability by priming proteins for ubiquitination, but it can also alter protein conformation and/or affinity for binding partners [70]; and thus could also regulate interactions between the core proteins and sorting of complexes. Interestingly, phosphorylation has been identified as a key modulator of phase transitions, and thus could regulate clustering of core protein complexes into puncta [71].

Table 3
Post-translational modifications of the core planar polarity proteins
SubstrateEnzymeCandidate modification sitesReferences
Fmi1 Fat facets (Faf) deubiquitinase [73
Celsr12 Polo-like kinase 1 (Plk1)2 14 S/T residues in the cytoplasmic domain of mouse Celsr1, including S2741, T2750, and S2752 [92
Fz atypical Protein Kinase C (aPKC) S554, S560 of fly Fz [95
Stbm
Vangl22 
Casein Kinase 1ε (CKIε)
Casein Kinase 1δ/ε (CKIδ/ε)2 
Two clusters of highly conserved S/T residues located in the N-terminal cytoplasmic domain (S5–17, ST113–122 of fly Dsh; S5–17, ST76–84 of mouse Vangl2) [61,88–91
Pk Farnesyl-diphosphate farnesyl transferase (FNTA, FNTB) C-terminal CaaX motif [75
Pk
Pk22 
Cullin1-SkpA-Slimb
Skp1-Cullin1-F-Box2
ubiquitin ligase 
[62,75,76
Pk12 Smurf12, Smurf22
ubiquitin ligases 
[77,78
Pk Nemo kinase 4 potential MAPK phosphorylation sites in the middle region [98
Pk1 Ste20 kinase Mink1 T370 of Xenopus Pk1 [53
Dsh
Dvl3 
Cullin3-Diablo/Kelch
Cullin3-KLHL123
ubiquitin ligase 
[72,73
Dsh Abelson tyrosine kinase (Abl) Y473 of fly Dsh [79,82
Dsh Nek2 kinase multiple sites [80,81
Dsh
Dvl2,3,4 
Casein Kinase 1ε (CKIε)
Casein Kinase 1δ/ε (CKIδ/ε)2,3,4 
S236 of fly Dsh [61,83–87
SubstrateEnzymeCandidate modification sitesReferences
Fmi1 Fat facets (Faf) deubiquitinase [73
Celsr12 Polo-like kinase 1 (Plk1)2 14 S/T residues in the cytoplasmic domain of mouse Celsr1, including S2741, T2750, and S2752 [92
Fz atypical Protein Kinase C (aPKC) S554, S560 of fly Fz [95
Stbm
Vangl22 
Casein Kinase 1ε (CKIε)
Casein Kinase 1δ/ε (CKIδ/ε)2 
Two clusters of highly conserved S/T residues located in the N-terminal cytoplasmic domain (S5–17, ST113–122 of fly Dsh; S5–17, ST76–84 of mouse Vangl2) [61,88–91
Pk Farnesyl-diphosphate farnesyl transferase (FNTA, FNTB) C-terminal CaaX motif [75
Pk
Pk22 
Cullin1-SkpA-Slimb
Skp1-Cullin1-F-Box2
ubiquitin ligase 
[62,75,76
Pk12 Smurf12, Smurf22
ubiquitin ligases 
[77,78
Pk Nemo kinase 4 potential MAPK phosphorylation sites in the middle region [98
Pk1 Ste20 kinase Mink1 T370 of Xenopus Pk1 [53
Dsh
Dvl3 
Cullin3-Diablo/Kelch
Cullin3-KLHL123
ubiquitin ligase 
[72,73
Dsh Abelson tyrosine kinase (Abl) Y473 of fly Dsh [79,82
Dsh Nek2 kinase multiple sites [80,81
Dsh
Dvl2,3,4 
Casein Kinase 1ε (CKIε)
Casein Kinase 1δ/ε (CKIδ/ε)2,3,4 
S236 of fly Dsh [61,83–87

See Table 1 for fly and vertebrate homologues. Modifications were of fly molecules unless otherwise stated.

1

Deduced target, but no direct modification observed;

2

Mouse;

3

human;

4

Xenopus.

Ubiquitination of Drosophila Dsh via a Cullin3-Diablo/Kelch ubiquitin ligase complex results in reduced Dsh at cell junctions and its targeting for degradation [72,73]. Dsh ubiquitination is antagonised by the phosphoinositide binding protein Kramer/PLEKHA4, which in vertebrates sequesters the Kelch homologue KLHL12 (Figure 2E) [74]. There is also evidence of ubiquitination promoting internalisation of Fmi, as the deubiquitinase Fat facets (Faf) promotes the recycling of internalised Fmi to the junctional membrane (Figure 2E) [73]. Furthermore, farnesylation of Pk promotes its recruitment into the proximal complex by Stbm [75], while Stbm also promotes degradation of excess Pk via a Cullin1–SkpA–Supernumerary limbs (Slimb) ubiquitin ligase complex (Figure 2E) [62,75,76]. In vertebrates, the HECT ubiquitin ligases Smurf1 and Smurf2 promote proteasomal degradation of Pk [77]. Interestingly, Smurfs also interact specifically with phosphorylated Dvl (the vertebrate Dsh homologue) [77], and Dvl promotes Smurf activity [78]. This leads to a model in which phosphorylated Dsh recruits Smurf, which then ubiquitinates Pk and destabilises complexes of the opposite orientation (Figure 2E).

The abundance of evidence for PTM control of planar polarity comes from assays of protein phosphorylation. In particular, Dsh hyperphosphorylation correlates with its recruitment to junctions by Fz [17,19], and analysis of putative phosphorylation sites in Dsh has revealed multiple redundant phosphorylation sites [79]. Phosphorylation of Dsh by the Abelson tyrosine kinase (Abl), Nek2 and Casein kinase Iε (CKIε, or Discs overgrown [Dco] in flies) has been implicated in regulation of planar polarity (Figure 2F). Nek2 phosphorylates Dsh at multiple sites [80] and loss of Nek2 leads to accumulation of Dsh in intracellular puncta, and reduced core protein asymmetry [81]. Abl phosphorylates Dsh in vitro at Tyr473, and loss of Abl disrupts photoreceptor specification and polarity [82]. Finally, CKIε promotes Dsh phosphorylation in vitro and in vivo, and loss of CKIε abolishes core protein asymmetry [61,83–88].

In addition to phosphorylating Dsh, CKIε also phosphorylates the N-terminus of Stbm, and mutation of the Stbm phosphorylation sites disrupts planar polarity in both flies and vertebrates [61,88–91]. Interestingly, in Drosophila mutation of the CKIε phosphorylation sites in Stbm leads to an increase in Stbm stability, while mutation of putative CKIε phosphorylation sites in Dsh decreases its stability (Figure 2F) [61]. This dual action of CKIε would therefore enhance removal of Stbm from complexes and stabilise Dsh in complexes, and thus promote sorting of proximal and distal complex components to opposite cell ends.

In vertebrate skin, the Fmi homologue Celsr1 is phosphorylated on a dileucine endocytic motif by Polo-like kinase 1 (Plk1) [92]. Interestingly, Plk1 is a mitotic kinase and thus promotes internalisation of Celsr1 specifically in mitosis (Figure 2F). Failure of this internalisation perturbs skin planar polarity [92,93]. Internalisation was suggested to allow core proteins to be redistributed equally between the two daughter cells, and also to protect mitotic cells against aberrant signalling while they are rounded up.

Three further kinases, atypical PKC (aPKC), Nemo and Misshapen (Msn) have also been implicated in regulating planar polarity in the Drosophila eye (Figure 2F) [94–96]. aPKC can phosphorylate the cytoplasmic tail of Fz, which is thought to inhibit Fz function. This activity of aPKC on Fz is antagonised by the apicobasal polarity protein Bazooka/Par-3 [95]. Bazooka also interacts with Fmi, raising interesting questions regarding cross-talk between apicobasal and planar polarity [97]. Nemo is thought to act in two ways in eye planar polarity: firstly, a direct effect via Pk [98] and secondly by regulating downstream effectors that regulate ommatidial cluster rotation [99]. Pk phosphorylation by Nemo is thought to promote the targeted proteasomal degradation of Pk from planar polarity complexes via Cullin1–SkpA–Slimb (see above) [98]. Finally, in vertebrates Pk phosphorylation by the Msn homologue Mink1 promotes Pk trafficking to the plasma membrane and clustering with the vertebrate Stbm homologue Vangl2 [53].

Future directions

It is interesting to note that despite the long list of known PTMs that affect core protein activity, only in the case of Smurf binding to phosphorylated Dsh has a specific regulatory mechanism been uncovered that implicates a PTM in driving core complex sorting within clusters. Nevertheless, it seems likely that spatiotemporal regulation of PTMs will be a critical mechanism in planar polarity establishment.

Integral to models of core protein sorting via feedback interactions is the idea that complexes in the same orientation are stabilised and those of the opposite orientation are destabilised (Figure 1J). To understand stabilising/destabilising interactions it will be necessary to identify the role of specific PTMs: in particular, how each PTM affects the stability of core proteins at junctions. It will also be important to determine whether and how specific PTMs are regulated: for example if one core protein locally promotes the modification of another protein and this alters its stability then this would constitute evidence for a feedback mechanism.

Moreover, understanding the complex roles of multiple PTMs will require precise spatiotemporal manipulations of protein activity, in order to distinguish fast acting direct effects from more long term consequences. This will require the development of new methods for acutely activating or removing activity. Finally, we anticipate that advances in microscopy — for instance single molecule imaging — that allow more detailed visualisation of core protein clustering at cell junctions, will be key in understanding the effects of specific PTMs on core protein organisation and sorting.

Such studies will be an important and exciting way forward in unravelling molecular mechanisms of core planar polarity pathway function.

Perspectives

  • Planar polarity allows cells and groups of cells to exhibit polarised behaviours that are co-ordinated with their neighbours and the tissue axes. Such coordination of cell behaviours is vital for correct tissue morphogenesis and function.

  • Co-ordinated planar polarisation involves the formation of heterophilic intercellular complexes that become asymmetrically localised to opposite cell edges. Self-organising processes involving stabilising and destabilising feedback interactions between intercellular complexes leads to clustering of complexes of the same orientation in puncta. PTMs most likely play a key role in controlling the spatiotemporal dynamics of planar polarity protein interactions.

  • Further research is required to elucidate the cellular mechanisms that sort the core proteins across the cell, and how the feedback interactions between the core planar polarity proteins are regulated. The control of PTMs is important in core protein asymmetry, however, the mechanisms controlling PTM activity are poorly understood. Better methods for mapping PTMs and PTM enzyme activity in time and space will be essential for understanding pathway function.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

Work in the Strutt laboratory is funded by a Wellcome Trust Senior Fellowship in Basic Biomedical Science (210630/Z/18/Z) to D.S.

Author Contributions

Literature review, C.H., H.S., H.S. and D.S.; Writing — original draft preparation, C.H. and H.S.; Writing — review and editing, C.H., H.S. and D.S.; Figure preparation, C.H. and H.S.; Table preparation, Hongyu Shao.

Acknowledgements

We thank Alexandre Carayon and Samantha Warrington for helpful comments on the manuscript.

Abbreviations

     
  • FRAP

    Fluorescence recovery after photobleaching

  •  
  • PCP

    planar cell polarity

  •  
  • PTMs

    Post-translational modifications

References

References
1
Hale
,
R.
and
Strutt
,
D.
(
2015
)
Conservation of planar polarity pathway function across the animal kingdom
.
Annu. Rev. Genet.
49
,
529
551
2
Goodrich
,
L.V.
and
Strutt
,
D.
(
2011
)
Principles of planar polarity in animal development
.
Development
138
,
1877
1892
3
Devenport
,
D.
(
2014
)
The cell biology of planar cell polarity
.
J. Cell Biol.
207
,
171
179
4
Butler
,
M.T.
and
Wallingford
,
J.B.
(
2017
)
Planar cell polarity in development and disease
.
Nat. Rev. Mol. Cell. Biol.
18
,
375
388
5
Gong
,
Y.
,
Mo
,
C.
and
Fraser
,
S.E.
(
2004
)
Planar cell polarity signalling controls cell division orientation during zebrafish gastrulation
.
Nature
430
,
689
693
6
Trichas
,
G.
,
Smith
,
A.M.
,
White
,
N.
,
Wilkins
,
V.
,
Watanabe
,
T.
,
Moore
,
A.
et al (
2012
)
Multi-cellular rosettes in the mouse visceral endoderm facilitate the ordered migration of anterior visceral endoderm cells
.
PLoS Biol.
10
,
e1001256
7
Wang
,
M.
,
Marco
,
P.
,
Capra
,
V.
and
Kibar
,
Z.
(
2019
)
Update on the role of the non-canonical Wnt/planar cell polarity pathway in neural tube defects
.
Cells
8
,
1198
8
Chen
,
H.
and
Cheng
,
C.Y.
(
2016
)
Planar cell polarity (PCP) proteins and spermatogenesis
.
Semin. Cell Dev. Biol.
59
,
99
109
9
Tower-Gilchrist
,
C.
,
Zlatic
,
S.A.
,
Yu
,
D.
,
Chang
,
Q.
,
Wu
,
H.
,
Lin
,
X.
et al (
2019
)
Adaptor protein-3 complex is required for Vangl2 trafficking and planar cell polarity of the inner ear
.
Mol. Biol. Cell
30
,
2422
2434
10
Henderson
,
D.J.
and
Chaudhry
,
B.
(
2011
)
Getting to the heart of planar cell polarity signaling
.
Birth Defects Res. A Clin. Mol. Teratol.
91
,
460
467
11
Ambegaonkar
,
A.A.
,
Pan
,
G.
,
Mani
,
M.
,
Feng
,
Y.
and
Irvine
,
K.D.
(
2012
)
Propagation of Dachsous-Fat planar cell polarity
.
Curr. Biol.
22
,
1302
1308
12
Bosveld
,
F.
,
Bonnet
,
I.
,
Guirao
,
B.
,
Tlili
,
S.
,
Wang
,
Z.
,
Petitalot
,
A.
et al (
2012
)
Mechanical control of morphogenesis by Fat/Dachsous/Four-jointed planar cell polarity pathway
.
Science
336
,
724
727
13
Brittle
,
A.
,
Thomas
,
C.
and
Strutt
,
D.
(
2012
)
Planar polarity specification through asymmetric subcellular localization of Fat and dachsous
.
Curr. Biol.
22
,
907
914
14
Ma
,
D.
,
Yang
,
C.H.
,
McNeill
,
H.
,
Simon
,
M.A.
and
Axelrod
,
J.D.
(
2003
)
Fidelity in planar cell polarity signalling
.
Nature
421
,
543
547
15
Matakatsu
,
H.
and
Blair
,
S.S.
(
2004
)
Interactions between Fat and Dachsous and the regulation of planar cell polarity in the drosophila wing
.
Development
131
,
3785
3794
16
Usui
,
T.
,
Shima
,
Y.
,
Shimada
,
Y.
,
Hirano
,
S.
,
Burgess
,
R.W.
,
Schwarz
,
T.L.
et al (
1999
)
Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of frizzled
.
Cell
98
,
585
595
17
Axelrod
,
J.D.
(
2001
)
Unipolar membrane association of dishevelled mediates frizzled planar cell polarity signaling
.
Genes Dev.
15
,
1182
1187
18
Feiguin
,
F.
,
Hannus
,
M.
,
Mlodzik
,
M.
and
Eaton
,
S.
(
2001
)
The ankyrin repeat protein Diego mediates Frizzled-dependent planar polarization
.
Dev. Cell
1
,
93
101
19
Shimada
,
Y.
,
Usui
,
T.
,
Yanagawa
,
S.
,
Takeichi
,
M.
and
Uemura
,
T.
(
2001
)
Asymmetric colocalization of Flamingo, a seven-pass transmembrane cadherin, and dishevelled in planar cell polarization
.
Curr. Biol.
11
,
859
863
20
Strutt
,
D.I.
(
2001
)
Asymmetric localization of Frizzled and the establishment of cell polarity in the Drosophila wing
.
Mol. Cell
7
,
367
375
21
Das
,
G.
,
Jenny
,
A.
,
Klein
,
T.J.
,
Eaton
,
S.
and
Mlodzik
,
M.
(
2004
)
Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes
.
Development
131
,
4467
4476
22
Tree
,
D.R.
,
Shulman
,
J.M.
,
Rousset
,
R.
,
Scott
,
M.P.
,
Gubb
,
D.
and
Axelrod
,
J.D.
(
2002
)
Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling
.
Cell
109
,
371
381
23
Bastock
,
R.
,
Strutt
,
H.
and
Strutt
,
D.
(
2003
)
Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning
.
Development
130
,
3007
3014
24
Zeidler
,
M.P.
,
Perrimon
,
N.
and
Strutt
,
D.I.
(
2000
)
Multiple rôles for four-jointed in planar polarity and limb patterning
.
Dev. Biol.
228
,
181
196
25
Strutt
,
H.
,
Mundy
,
J.
,
Hofstra
,
K.
and
Strutt
,
D.
(
2004
)
Cleavage and secretion is not required for four-jointed function in Drosophila patterning
.
Development
131
,
881
890
26
Brittle
,
A.L.
,
Repiso
,
A.
,
Casal
,
J.
,
Lawrence
,
P.A.
and
Strutt
,
D.
(
2010
)
Four-Jointed modulates growth and planar polarity by reducing the affinity of Dachsous for Fat
.
Curr. Biol.
20
,
803
810
27
Simon
,
M.A.
,
Xu
,
A.
,
Ishikawa
,
H.O.
and
Irvine
,
K.D.
(
2010
)
Modulation of Fat:Dachsous binding by the cadherin domain kinase four-Jointed
.
Curr. Biol.
20
,
811
817
28
Hale
,
R.
,
Brittle
,
A.L.
,
Fisher
,
K.H.
,
Monk
,
N.A.
and
Strutt
,
D.
(
2015
)
Cellular interpretation of the long-range gradient of four-jointed activity in the Drosophila wing
.
eLife
4
,
e05789
29
Bhanot
,
P.
,
Brink
,
M.
,
Samos
,
C.H.
,
Hsieh
,
J.-C.
,
Wang
,
Y.
,
Macke
,
J.P.
et al (
1996
)
A new member of the frizzled family from Drosophila functions as a wingless receptor
.
Nature
382
,
225
230
30
Strigini
,
M.
and
Cohen
,
S.M.
(
1999
)
Formation of morphogen gradients in the Drosophila wing
.
Semin. Cell Dev. Biol.
10
,
335
344
31
Gieseler
,
K.
,
Wilder
,
E.
,
Mariol
,
M.C.
,
Buratovitch
,
M.
,
Berenger
,
H.
,
Graba
,
Y.
et al (
2001
)
DWnt4 and wingless elicit similar cellular responses during imaginal development
.
Dev. Biol.
232
,
339
350
32
Janson
,
K.
,
Cohen
,
E.D.
and
Wilder
,
E.L.
(
2001
)
Expression of DWnt6, DWnt10, and DFz4 during Drosophila development
.
Mech. Dev.
103
,
117
120
33
Wu
,
J.
,
Roman
,
A.C.
,
Carvajal-Gonzalez
,
J.M.
and
Mlodzik
,
M.
(
2013
)
Wg and Wnt4 provide long-range directional input to planar cell polarity orientation in drosophila
.
Nat. Cell Biol.
15
,
1045
1055
34
Aw
,
W.Y.
and
Devenport
,
D.
(
2016
)
Planar cell polarity: global inputs establishing cellular asymmetry
.
Curr. Opin. Cell Biol.
44
,
110
116
35
Sagner
,
A.
,
Merkel
,
M.
,
Aigouy
,
B.
,
Gaebel
,
J.
,
Brankatschk
,
M.
,
Julicher
,
F.
et al (
2012
)
Establishment of global patterns of planar polarity during growth of the drosophila wing epithelium
.
Curr. Biol.
22
,
1296
1301
36
Classen
,
A.K.
,
Anderson
,
K.I.
,
Marois
,
E.
and
Eaton
,
S.
(
2005
)
Hexagonal packing of drosophila wing epithelial cells by the planar cell polarity pathway
.
Dev. Cell
9
,
805
817
37
Aigouy
,
B.
,
Farhadifar
,
R.
,
Staple
,
D.B.
,
Sagner
,
A.
,
Röper
,
J.-C.
,
Julicher
,
F.
et al (
2010
)
Cell flow reorients the axis of planar polarity in the wing epithelium of Drosophila
.
Cell
142
,
773
786
38
Strutt
,
H.
and
Strutt
,
D.
(
2008
)
Differential stability of Flamingo protein complexes underlies the establishment of planar polarity
.
Curr. Biol.
18
,
1555
1564
39
Struhl
,
G.
,
Casal
,
J.
and
Lawrence
,
P.A.
(
2012
)
Dissecting the molecular bridges that mediate the function of Frizzled in planar cell polarity
.
Development
139
,
3665
3674
40
Shimada
,
Y.
,
Yonemura
,
S.
,
Ohkura
,
H.
,
Strutt
,
D.
and
Uemura
,
T.
(
2006
)
Polarized transport of Frizzled along the planar microtubule arrays in Drosophila wing epithelium
.
Dev. Cell
10
,
209
222
41
Matis
,
M.
,
Russler-Germain
,
D.A.
,
Hu
,
Q.
,
Tomlin
,
C.J.
and
Axelrod
,
J.D.
(
2014
)
Microtubules provide directional information for core PCP function
.
eLife
3
,
e02893
42
Strutt
,
D.
and
Strutt
,
H.
(
2007
)
Differential activities of the core planar polarity proteins during Drosophila wing patterning
.
Dev. Biol.
302
,
181
194
43
Chen
,
W.S.
,
Antic
,
D.
,
Matis
,
M.
,
Logan
,
C.Y.
,
Povelones
,
M.
,
Anderson
,
G.A.
et al (
2008
)
Asymmetric homotypic interactions of the atypical cadherin Flamingo mediate intercellular polarity signaling
.
Cell
133
,
1093
1105
44
Vinson
,
C.R.
and
Adler
,
P.N.
(
1987
)
Directional non-cell autonomy and the transmission of polarity information by the frizzled gene of Drosophila
.
Nature
329
,
549
551
45
Park
,
M.
and
Moon
,
R.T.
(
2002
)
The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos
.
Nat. Cell Biol.
4
,
20
25
46
Jenny
,
A.
,
Darken
,
R.S.
,
Wilson
,
P.A.
and
Mlodzik
,
M.
(
2003
)
Prickle and strabismus form a functional complex to generate a correct axis during planar cell polarity signaling
.
EMBO J.
22
,
4409
4420
47
Takeuchi
,
M.
,
Nakabayashi
,
J.
,
Sakaguchi
,
T.
,
Yamamoto
,
T.S.
,
Takahashi
,
H.
,
Takeda
,
H.
et al (
2003
)
The prickle-related gene in vertebrates is essential for gastrulation cell movements
.
Curr. Biol.
13
,
674
679
48
Torban
,
E.
,
Wang
,
H.J.
,
Groulx
,
N.
and
Gros
,
P.
(
2004
)
Independent mutations in mouse Vangl2 that cause neural tube defects in looptail mice impair interaction with members of the dishevelled family
.
J. Biol. Chem.
279
,
52703
52713
49
Jenny
,
A.
,
Reynolds-Kenneally
,
J.
,
Das
,
G.
,
Burnett
,
M.
and
Mlodzik
,
M.
(
2005
)
Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for dishevelled binding
.
Nat. Cell Biol.
7
,
691
697
50
Moeller
,
H.
,
Jenny
,
A.
,
Schaeffer
,
H.J.
,
Schwarz-Romond
,
T.
,
Mlodzik
,
M.
,
Hammerschmidt
,
M.
et al (
2006
)
Diversin regulates heart formation and gastrulation movements in development
.
Proc. Natl Acad. Sci. U.S.A.
103
,
15900
15905
51
Montcouquiol
,
M.
,
Sans
,
N.
,
Huss
,
D.
,
Kach
,
J.
,
Dickman
,
J.D.
,
Forge
,
A.
et al (
2006
)
Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals
.
J. Neurosci.
26
,
5265
5275
52
Devenport
,
D.
and
Fuchs
,
E.
(
2008
)
Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles
.
Nat. Cell Biol.
10
,
1257
1268
53
Daulat
,
A.M.
,
Luu
,
O.
,
Sing
,
A.
,
Zhang
,
L.
,
Wrana
,
J.L.
,
McNeill
,
H.
et al (
2012
)
Mink1 regulates beta-catenin-independent Wnt signaling via Prickle phosphorylation
.
Mol. Cell. Biol.
32
,
173
185
54
Belotti
,
E.
,
Puvirajesinghe
,
T.M.
,
Audebert
,
S.
,
Baudelet
,
E.
,
Camoin
,
L.
,
Pierres
,
M.
et al (
2012
)
Molecular characterisation of endogenous Vangl2/Vangl1 heteromeric protein complexes
.
PLoS ONE
7
,
e46213
55
Tauriello
,
D.V.
,
Jordens
,
I.
,
Kirchner
,
K.
,
Slootstra
,
J.W.
,
Kruitwagen
,
T.
,
Bouwman
,
B.A.
et al (
2012
)
Wnt/beta-catenin signaling requires interaction of the dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled
.
Proc. Natl Acad. Sci. U.S.A.
109
,
E812
E820
56
Amonlirdviman
,
K.
,
Khare
,
N.A.
,
Tree
,
D.R.
,
Chen
,
W.S.
,
Axelrod
,
J.D.
and
Tomlin
,
C.J.
(
2005
)
Mathematical modeling of planar cell polarity to understand domineering nonautonomy
.
Science
307
,
423
426
57
Le Garrec
,
J.F.
,
Lopez
,
P.
and
Kerszberg
,
M.
(
2006
)
Establishment and maintenance of planar epithelial cell polarity by asymmetric cadherin bridges: a computer model
.
Dev. Dyn.
235
,
235
246
58
Burak
,
Y.
and
Shraiman
,
B.I.
(
2009
)
Order and stochastic dynamics in Drosophila planar cell polarity
.
PLoS Comput. Biol.
5
,
e1000628
59
Schamberg
,
S.
,
Houston
,
P.
,
Monk
,
N.A.
and
Owen
,
M.R.
(
2010
)
Modelling and analysis of planar cell polarity
.
Bull. Math. Biol.
72
,
645
680
60
Warrington
,
S.J.
,
Strutt
,
H.
,
Fisher
,
K.H.
and
Strutt
,
D.
(
2017
)
A dual function for Prickle in regulating Frizzled stability during feedback-dependent amplification of planar polarity
.
Curr. Biol.
27
,
2784
2797
61
Strutt
,
H.
,
Gamage
,
J.
and
Strutt
,
D.
(
2019
)
Reciprocal action of casein kinase I epsilon on core planar polarity proteins regulates clustering and asymmetric localisation
.
eLife
8
,
e45107
62
Cho
,
B.
,
Pierre-Louis
,
G.
,
Sagner
,
A.
,
Eaton
,
S.
and
Axelrod
,
J.D.
(
2015
)
Clustering and negative feedback by endocytosis in planar cell polarity signaling is modulated by ubiquitinylation of prickle
.
PLoS Genet.
11
,
e1005259
63
Ressurreicao
,
M.
,
Warrington
,
S.
and
Strutt
,
D.
(
2018
)
Rapid disruption of dishevelled activity uncovers an intercellular role in maintenance of Prickle in core planar polarity protein complexes
.
Cell Rep.
25
,
1415
1424
64
Strutt
,
H.
,
Warrington
,
S.J.
and
Strutt
,
D.
(
2011
)
Dynamics of core planar polarity protein turnover and stable assembly into discrete membrane subdomains
.
Dev. Cell
20
,
511
525
65
Strutt
,
H.
,
Gamage
,
J.
and
Strutt
,
D.
(
2016
)
Robust asymmetric localization of planar polarity proteins is associated with organization into signalosome-like domains of variable stoichiometry
.
Cell. Rep.
17
,
2660
2671
66
Chiou
,
J.G.
,
Balasubramanian
,
M.K.
and
Lew
,
D.J.
(
2017
)
Cell polarity in yeast
.
Annu. Rev. Cell Dev. Biol.
33
,
77
101
67
Lang
,
C.F.
and
Munro
,
E.
(
2017
)
The PAR proteins: from molecular circuits to dynamic self-stabilizing cell polarity
.
Development
144
,
3405
3416
68
St Johnston
,
D.
(
2018
)
Establishing and transducing cell polarity: common themes and variations
.
Curr. Opin. Cell Biol.
51
,
33
41
69
Clague
,
M.J.
and
Urbe
,
S.
(
2010
)
Ubiquitin: same molecule, different degradation pathways
.
Cell
143
,
682
685
70
Hunter
,
T.
(
2007
)
The age of crosstalk: phosphorylation, ubiquitination, and beyond
.
Mol. Cell
28
,
730
738
71
Snead
,
W.T.
and
Gladfelter
,
A.S.
(
2019
)
The control centers of biomolecular phase separation: how membrane surfaces, PTMs, and active processes regulate condensation
.
Mol. Cell
76
,
295
305
72
Angers
,
S.
,
Thorpe
,
C.J.
,
Biechele
,
T.L.
,
Goldenberg
,
S.J.
,
Zheng
,
N.
,
MacCoss
,
M.J.
et al (
2006
)
The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting dishevelled for degradation
.
Nat. Cell Biol.
8
,
348
357
73
Strutt
,
H.
,
Searle
,
E.
,
Thomas-Macarthur
,
V.
,
Brookfield
,
R.
and
Strutt
,
D.
(
2013
)
A Cul-3-BTB ubiquitylation pathway regulates junctional levels and asymmetry of core planar polarity proteins
.
Development
140
,
1693
1702
74
Shah A.
,
S.
,
Batrouni
,
A.G.
,
Kim
,
D.
,
Punyala
,
A.
,
Cao
,
W.
,
Han
,
C.
et al (
2019
)
PLEKHA4/kramer attenuates dishevelled ubiquitination to modulate Wnt and planar cell polarity signaling
.
Cell Rep.
27
,
2157
2170
75
Strutt
,
H.
,
Thomas-MacArthur
,
V.
and
Strutt
,
D.
(
2013
)
Strabismus promotes recruitment and degradation of farnesylated prickle in Drosophila melanogaster planar polarity specification
.
PLoS Genet.
9
,
e1003654
76
Nagaoka
,
T.
,
Furuse
,
M.
,
Ohtsuka
,
T.
,
Tsuchida
,
K.
and
Kishi
,
M.
(
2019
)
Vangl2 interaction plays a role in the proteasomal degradation of Prickle2
.
Sci. Rep.
9
,
2912
77
Narimatsu
,
M.
,
Bose
,
R.
,
Pye
,
M.
,
Zhang
,
L.
,
Miller
,
B.
,
Ching
,
P.
et al (
2009
)
Regulation of planar cell polarity by smurf ubiquitin ligases
.
Cell
137
,
295
307
78
Bernatik
,
O.
,
Paclikova
,
P.
,
Sri Ganji
,
R.
and
Bryja
,
V.
(
2020
)
Activity of Smurf2 ubiquitin ligase Is regulated by the Wnt pathway protein dishevelled
.
Cells
9
,
1147
79
Yanfeng
,
W.A.
,
Berhane
,
H.
,
Mola
,
M.
,
Singh
,
J.
,
Jenny
,
A.
and
Mlodzik
,
M.
(
2011
)
Functional dissection of phosphorylation of disheveled in drosophila
.
Dev. Biol.
360
,
132
142
80
Schertel
,
C.
,
Huang
,
D.
,
Bjorklund
,
M.
,
Bischof
,
J.
,
Yin
,
D.
,
Li
,
R.
et al (
2013
)
Systematic screening of a Drosophila ORF library in vivo uncovers Wnt/Wg pathway components
.
Dev. Cell
25
,
207
219
81
Weber
,
U.
and
Mlodzik
,
M.
(
2017
)
APC/c(Fzr/Cdh1)-dependent regulation of planar cell polarity establishment via Nek2 kinase acting on dishevelled
.
Dev. Cell
40
,
53
66
82
Singh
,
J.
,
Yanfeng
,
W.A.
,
Grumolato
,
L.
,
Aaronson
,
S.A.
and
Mlodzik
,
M.
(
2010
)
Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation
.
Genes Dev.
24
,
2157
2168
83
Peters
,
J.M.
,
McKay
,
R.M.
,
McKay
,
J.P.
and
Graff
,
J.M.
(
1999
)
Casein kinase I transduces Wnt signals
.
Nature
401
,
345
350
84
Sakanaka
,
C.
,
Leong
,
P.
,
Xu
,
L.
,
Harrison
,
S.D.
and
Williams
,
L.T.
(
1999
)
Casein kinase Iε in the Wnt pathway: Regulation of β-catenin function
.
Proc. Natl Acad. Sci. U.S.A.
96
,
12548
12552
85
Cong
,
F.
,
Schweizer
,
L.
and
Varmus
,
H.
(
2004
)
Casein kinase Iε modulates the signaling specificities of dishevelled
.
Mol. Cell. Biol.
24
,
2000
2011
86
Klein
,
T.J.
,
Jenny
,
A.
,
Djiane
,
A.
and
Mlodzik
,
M.
(
2006
)
CKIepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in drosophila
.
Curr. Biol.
16
,
1337
1343
87
Strutt
,
H.
,
Price
,
M.A.
and
Strutt
,
D.
(
2006
)
Planar polarity is positively regulated by casein kinase iepsilon in drosophila
.
Curr. Biol.
16
,
1329
1336
88
Kelly
,
L.K.
,
Wu
,
J.
,
Yanfeng
,
W.A.
and
Mlodzik
,
M.
(
2016
)
Frizzled-induced Van Gogh phosphorylation by CK1epsilon promotes asymmetric localization of core PCP factors in Drosophila
.
Cell Rep.
16
,
344
356
89
Gao
,
B.
,
Song
,
H.
,
Bishop
,
K.
,
Elliot
,
G.
,
Garrett
,
L.
,
English
,
M.A.
et al (
2011
)
Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2
.
Dev. Cell
20
,
163
176
90
Ossipova
,
O.
,
Kim
,
K.
and
Sokol
,
S.Y.
(
2015
)
Planar polarization of Vangl2 in the vertebrate neural plate is controlled by Wnt and Myosin II signaling
.
Biol. Open.
4
,
722
730
91
Yang
,
W.
,
Garrett
,
L.
,
Feng
,
D.
,
Elliott
,
G.
,
Liu
,
X.
,
Wang
,
N.
et al (
2017
)
Wnt-induced Vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development
.
Cell Res.
27
,
1466
1484
92
Shrestha
,
R.
,
Little
,
K.A.
,
Tamayo
,
J.V.
,
Li
,
W.
,
Perlman
,
D.H.
and
Devenport
,
D.
(
2015
)
Mitotic control of planar cell polarity by Polo-like kinase 1
.
Dev. Cell
33
,
522
534
93
Devenport
,
D.
,
Oristian
,
D.
,
Heller
,
E.
and
Fuchs
,
E.
(
2011
)
Mitotic internalization of planar cell polarity proteins preserves tissue polarity
.
Nat. Cell Biol.
13
,
893
902
94
Choi
,
K.W.
and
Benzer
,
S.
(
1994
)
Rotation of photoreceptor clusters in the developing Drosophila eye requires the nemo gene
.
Cell
78
,
125
136
95
Djiane
,
A.
and
Mlodzik M
,
S.Y.
(
2005
)
The apical determinants aPKC and dPatj regulate Frizzled-dependent planar cell polarity in the Drosophila eye
.
Cell
121
,
621
631
96
Paricio
,
N.
,
Feiguin
,
F.
,
Boutros
,
M.
,
Eaton
,
S.
and
Mlodzik
,
M.
(
1999
)
The Drosophila STE20-like kinase misshapen is required downstream of the Frizzled receptor in planar polarity signaling
.
EMBO J.
18
,
4669
4678
97
Wasserscheid
,
I.
,
Thomas
,
U.
and
Knust
,
E.
(
2007
)
Isoform-specific interaction of Flamingo/Starry Night with excess Bazooka affects planar cell polarity in the Drosophila wing
.
Dev. Dyn.
236
,
1064
1071
98
Collu
,
G.M.
,
Jenny
,
A.
,
Gaengel
,
K.
,
Mirkovic
,
I.
,
Chin
,
M.L.
,
Weber
,
U.
et al (
2018
)
Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment
.
PLoS Genet.
14
,
e1007391
99
Mirkovic
,
I.
,
Gault
,
W.J.
,
Rahnama
,
M.
,
Jenny
,
A.
,
Gaengel
,
K.
,
Bessette
,
D.
et al (
2011
)
Nemo kinase phosphorylates beta-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-beta-catenin
.
Nat. Struct. Mol. Biol.
18
,
665
672
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).