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

Developmental Cell
Shuijie LiSusanne Schlisio

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.

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Citations

Jan 10, 2018·The Journal of Physiology·Bong Sook JhunShey-Shing Sheu
Mar 13, 2019·Molecular Carcinogenesis·Koji AndoAkira Nakagawara
Dec 7, 2019·Journal of Experimental & Clinical Cancer Research : CR·Lucia CappabiancaAndrew Reay Mackay
Aug 4, 2019·Proceedings of the National Academy of Sciences of the United States of America·Shuijie LiSusanne Schlisio
Jan 30, 2018·Japanese Journal of Clinical Oncology·Akira NakagawaraMasanori Nishi
Apr 30, 2021·Journal of Cell Science·Antonina J Kruppa, Folma Buss

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