1. The 1p36 Tumor Suppressor KIF 1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis
- Author
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John Inge Johnsen, Olga Surova, Susanne Schlisio, Erik Smedler, Zhi Xiong Chen, Per Uhlén, Karin Wallis, Rajappa S. Kenchappa, Shuijie Li, Tommy Martinsson, Stuart M. Fell, Per Kogner, and Ulf Hellman
- Subjects
0301 basic medicine ,Phosphatase ,Cell Biology ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Dephosphorylation ,Calcineurin ,03 medical and health sciences ,030104 developmental biology ,Biochemistry ,Apoptosis ,Neuroblastoma ,medicine ,Phosphorylation ,Mitochondrial fission ,Signal transduction ,Molecular Biology ,Developmental Biology - 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.
- Published
- 2016
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