The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis
2016 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 36, no 2, 164-178 p.Article in journal (Refereed) PublishedText
KIF1B beta is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1B beta activates the Ca2+-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 Ca2+ signals and its deregulation is implicated in cancer, cardiac, neurodegenerative, and immune disease. We show that KIF1B beta affects mitochondria! dynamics through CN-dependent dephosphorylation of Dynamin-related protein 1 (DRP1), causing mitochondria! fission and apoptosis. Furthermore, KIF1B beta actuates recognition of all known CN substrates, implying a general mechanism for KIF1B beta in Ca2+ signaling and how Ca2+-dependent signaling is executed by CN. Pathogenic KIF1B beta mutations previously identified in neuroblastomas and pheochromocytomas all fail to activate CN or stimulate DRP1 dephosphorylation. Importantly, KIF1B beta and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondria! dynamics contributes to high-risk and poor-prognosis neuroblastoma.
Place, publisher, year, edition, pages
2016. Vol. 36, no 2, 164-178 p.
Cancer and Oncology
IdentifiersURN: urn:nbn:se:uu:diva-279628DOI: 10.1016/j.devcel.2015.12.029ISI: 000369353400007PubMedID: 26812016OAI: oai:DiVA.org:uu-279628DiVA: diva2:910014
FunderSwedish Childhood Cancer FoundationSwedish Research CouncilSwedish Cancer SocietySwedish Research Council