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The 1p36 Tumor Suppressor KIF 1B beta Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis

Journal article
Authors S. J. Li
S. M. Fell
O. Surova
Erik Smedler
K. Wallis
Z. X. Chen
U. Hellman
J. I. Johnsen
Tommy Martinsson
R. S. Kenchappa
P. Uhlen
P. Kogner
S. Schlisio
Published in Developmental Cell
Volume 36
Issue 2
Pages 164-178
ISSN 1534-5807
Publication year 2016
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages 164-178
Language en
Links dx.doi.org/10.1016/j.devcel.2015.12...
Keywords dependent protein-kinase, chromosome 1p36.2, cell-death, neuroblastoma, gene, drp1, dephosphorylation, phosphorylation, translocation, endocytosis, Cell Biology, Developmental Biology
Subject categories Medical Genetics

Abstract

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.

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