title: The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles.
abstract: Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events.
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Mariam H
authors.initials: MH
authors.lastname: Orme
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Liccardi
authors.affiliation: John Vane Science Centre, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Nina
authors.initials: N
authors.lastname: Moderau
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Feltham
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Sidonie
authors.initials: S
authors.lastname: Wicky-John
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Tencho
authors.initials: T
authors.lastname: Tenev
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, 1307 Meyer Building, Rehovot 76100, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Aram
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Bianchi
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Otto
authors.initials: O
authors.lastname: Morris
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Celia
authors.initials: C
authors.lastname: Monteiro Domingues
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.affiliation: University of Massachusetts Medical School, 364 Plantation Street, RB Suite 419, Worcester Massachusetts 01605, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Tare
authors.affiliation: ETH, Institute for Molecular Systems Biology, Wolfgang Pauli-Strasse 16, CH-8093 Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wepf
authors.affiliation: UCLA David Geffen School of Medicine, 200 Stein Plaza, Los Angeles, California 90095-7008, USA.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: University of Massachusetts Medical School, 364 Plantation Street, RB Suite 419, Worcester Massachusetts 01605, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: ETH, Institute for Molecular Systems Biology, Wolfgang Pauli-Strasse 16, CH-8093 Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gstaiger
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, 1307 Meyer Building, Rehovot 76100, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Arama
authors.affiliation: John Vane Science Centre, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Ribeiro
authors.affiliation: Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018613:Microscopy, Confocal; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal
chemical_list: D029721:Drosophila Proteins; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; C514773:ck protein, Drosophila; C000631458:myosin 7a, Drosophila; D000071679:Glycogen Synthase Kinase 3 beta; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3; D053181:Caspase 8; D020169:Caspases; C118731:dronc protein, Drosophila; D009218:Myosins