title: Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation.
abstract: Abelson (Abl) family tyrosine kinases have been implicated in cell morphogenesis, adhesion, motility, and oncogenesis. Using a candidate approach for genes involved in planar cell polarity (PCP) signaling, we identified Drosophila Abl (dAbl) as a modulator of Frizzled(Fz)/PCP signaling. We demonstrate that dAbl positively regulates the Fz/Dishevelled (Dsh) PCP pathway without affecting canonical Wnt/Wg-Fz signaling. Genetic dissection suggests that Abl functions via Fz/Dsh signaling in photoreceptor R3 specification, a well-established Fz-PCP signaling readout. Molecular analysis shows that dAbl binds and phosphorylates Dsh on Tyr473 within the DEP domain. This phosphorylation event on Dsh is functionally critical, as the equivalent DshY473F mutant is nonfunctional in PCP signaling and stable membrane association, although it rescues canonical Wnt signaling. Strikingly, mouse embryonic fibroblasts (MEFs) deficient for Abl1 and Abl2/Arg genes also show reduced Dvl2 phosphorylation as compared with control MEFs, and this correlates with a change in subcellular localization of endogenous Dvl2. As in Drosophila, such Abl-deficient MEFs show no change in canonical Wnt signaling. Taken together, our results argue for a conserved role of Abl family members in the positive regulation of Dsh activity toward Fz-Dsh/PCP signaling by Dsh phosphorylation.
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Jaskirat
authors.initials: J
authors.lastname: Singh
authors.forename: Wang A
authors.initials: WA
authors.lastname: Yanfeng
authors.forename: Luca
authors.initials: L
authors.lastname: Grumolato
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
authors.forename: Marek
authors.initials: M
authors.lastname: Mlodzik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D016764:Cell Polarity; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology; D051157:Frizzled Receptors / Q000378:metabolism*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C000606582:Dvl2 protein, mouse; D051157:Frizzled Receptors; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; C000606588:dsh protein, Drosophila; C058784:fz protein, Drosophila; D011505:Protein-Tyrosine Kinases; C506548:Abl protein, Drosophila