1. The 1p36 Tumor Suppressor KIF 1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis.
- Author
-
Li S, Fell SM, Surova O, Smedler E, Wallis K, Chen ZX, Hellman U, Johnsen JI, Martinsson T, Kenchappa RS, Uhlén P, Kogner P, and Schlisio S
- Subjects
- Dynamins, Genes, Tumor Suppressor physiology, Humans, Kinesins metabolism, Neuroblastoma genetics, Neuroblastoma metabolism, Phosphorylation, Signal Transduction genetics, Apoptosis genetics, Calcineurin genetics, GTP Phosphohydrolases genetics, Kinesins genetics, Microtubule-Associated Proteins genetics, Mitochondrial Dynamics genetics, Mitochondrial Proteins genetics, Mutation genetics
- 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF