Nemo kinase phosphorylates β-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin–β-catenin

Abstract

Frizzled/planar cell polarity (PCP) signaling regulates cell motility in several tissues, including ommatidial rotation in Drosophila melanogaster. The Nemo kinase has also been linked to cell motility regulation and ommatidial rotation. The mechanistic role(s) of Nemo during rotation remain however obscure. We demonstrate that nemo functions throughout the entire rotation movement promoting rate of rotation. Genetic and molecular studies indicate that Nemo binds both the core PCP factor complex of Strabismus–Prickle, and the E-cadherin–β-catenin (Armadillo) complex, which colocalize and like Nemo also promote rotation. Strabismus/Vang binds and stabilizes Nemo asymmetrically within the ommatidial precluster. Nemo and β-catenin then act synergistically promoting rotation, which is mediated in vivo through Nemo phosphorylation of β-catenin. Our data suggest that Nemo serves as a conserved molecular link between core PCP factors and E-cad/β-catenin complexes, promoting ommatidial rotation and cell motility in general.

Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal

“…Fzd6 has been associated with noncanonical Wnt signaling (13,14) with the potential to inhibit b-catenin-dependent canonical Wnt pathway in nonhematopoietic cells (15,29). In contrast, Fzd6 expression correlated with increased levels of intracellular bcatenin in a mouse model of chronic B lymphocytic leukemia although there was no evidence of a direct functional relationship (30).…”

“…Fzd6 expression has been demonstrated in HSPCs and mature blood-forming cells in human and mouse (26) with the strongest expression levels corresponding to more immature cell types (27,28). Fzd6 is generally associated with PCP signaling in epithelial cells (10,11,13,14), and it has been previously proposed to act as a negative regulator of the b-catenin-dependent canonical Wnt pathway (15,29). Very little is known about the functional role of Fzd6 signaling in the hematopoietic lineage, except for its being involved in the initiation and progression of chronic lymphocytic leukemia in the Em-TCL1 mouse model (30).…”

“…Although noncanonical, b-catenin-independent, Wnt signaling pathways are known to modulate cell polarity, cell motility, and tissue patterning (10)(11)(12)(13)(14)(15)(16)(17), their role in hematopoietic cells is much less well established. Exogenous Wnt5a has been shown to activate b-catenin-independent signaling in Lin 2 Sca1 + c-Kit hi (LSK) hematopoietic progenitors and to improve HSPC maintenance and function by promoting their quiescence (18)(19)(20)(21).…”

Novel Regulators of Planar Cell Polarity: A Genetic Analysis in Drosophila

“…This defect is accompanied by genetic interactions with Fz and Stan/Fmi among the core PCP genes. Furthermore, gish interacts with nemo (Mirkovic et al 2011) in this context in a specific manner: Gish/CK1g and Nemo act in opposition to each other (Figure 9), suggesting that a fine balance between the activities of these two kinases is required for normal ommatidial rotation to occur. Second, gish/CG6963 knockdown displays a high frequency of multiple cellular hairs, which is independent of a direct interaction with the core PCP factors (Gault et al 2012).…”

“…This is consistent with the interaction detected in the original screen genotype (a GOF dgo background) and it suggested a specific role for gish in ommatidial rotation. Next we asked whether any of the "rotation-specific PCP genes," including nemo (nmo, Nlk in mammals) (Choi and Benzer 1994;Fiehler and Wolff 2008;Mirkovic et al 2011), Rho-kinase (dRok in Drosophila) (Winter et al 2001), or zipper (zip, myosin II) (Fiehler and Wolff 2007), display a specific interaction with gish in this process. Of these, nmo displayed an antagonistic interaction with gish; whereas gish IR knockdown enhanced the sevGAL4, UAS-Nmo phenotype (Figure 9, E-F), the respective sevGAL4, UAS-gish IR knockdown phenotype was suppressed by dosage reduction of nmo (nmo DB /+; Figure 9G, see also Figure S3B for quantification).…”