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

KIF1Bβ is a candidate 1p36 tumor suppressor that regulates apoptosis in the developing sympathetic nervous system. We found that KIF1Bβ 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 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 Ca²⁺ signaling and how Ca²⁺-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. KIF1Bβ is a regulator of apoptosis and a candidate tumor suppressor, located in a chromosomal region frequently deleted in neuroblastoma. Li et al. now delineate the mechanism underlying these effects, showing that KIF1Bβ activates calcineurin, which in turn regulates mitochondrial dynamics via regulation of the mitochondrial fission protein DRP1.