title: The 1p36 Tumor Suppressor KIF 1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis.
abstract: KIF1Bβ is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1Bβ activates the Ca(2+)-dependent phosphatase calcineurin (CN) by stabilizing the CN-calmodulin complex, relieving enzymatic autoinhibition and enabling CN substrate recognition. CN is the key mediator of cellular responses to Ca(2+) signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1Bβ affects mitochondrial dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondrial fission and apoptosis. Furthermore, KIF1Bβ actuates recognition of all known CN substrates, implying a general mechanism for KIF1Bβ in Ca(2+) signaling and how Ca(2+)-dependent signaling is executed by CN. Pathogenic KIF1Bβ mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1Bβ and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondrial dynamics contributes to high-risk and poor-prognosis neuroblastoma.
authors.affiliation: Ludwig Institute for Cancer Research Ltd., 17177 Stockholm, Sweden; Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Shuijie
authors.initials: S
authors.lastname: Li
authors.affiliation: Ludwig Institute for Cancer Research Ltd., 17177 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Fell
authors.affiliation: Ludwig Institute for Cancer Research Ltd., 17177 Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Surova
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Smedler
authors.affiliation: Ludwig Institute for Cancer Research Ltd., 17177 Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Wallis
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Zhi Xiong
authors.initials: ZX
authors.lastname: Chen
authors.affiliation: Ludwig Institute for Cancer Research Ltd., Biomedical Center, 75124 Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hellman
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.affiliation: Department of Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, 41345 Göteborg, Sweden.
authors.forename: Tommy
authors.initials: T
authors.lastname: Martinsson
authors.affiliation: Neuro-Oncology Program, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, 17176 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Ludwig Institute for Cancer Research Ltd., 17177 Stockholm, Sweden; Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: susanne.schlisio@licr.ki.se.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schlisio
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D019703:Calcineurin / Q000235:genetics*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics
chemical_list: C091053:KIF1B protein, human; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D019703:Calcineurin; D020558:GTP Phosphohydrolases; D016547:Kinesins; C110768:DNM1L protein, human; D034281:Dynamins