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

Authors :
Li, Shuijie
Fell, Stuart M.
Surova, Olga
Smedler, Erik
Wallis, Karin
Chen, Zhi Xiong
Hellman, Ulf
Johnsen, John Inge
Martinsson, Tommy
Kenchappa, Rajappa S.
Uhlén, Per
Kogner, Per
Schlisio, Susanne
Source :
Developmental Cell. Jan2016, Vol. 36 Issue 2, p164-178. 15p.
Publication Year :
2016

Abstract

Summary 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15345807
Volume :
36
Issue :
2
Database :
Academic Search Index
Journal :
Developmental Cell
Publication Type :
Academic Journal
Accession number :
112389716
Full Text :
https://doi.org/10.1016/j.devcel.2015.12.029