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

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.

XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis

“…Conditional KIF1Bβ Knock-out (KO) mouse was generated by Dr. Susanne Schlisio's laboratory as described previously [21]. Briefly, the constitutive KO alleles specific for KIF1Bβ-isoform were obtained by crossing transgenic mice expressing Dopamine β-hydroxylase-Cre recombinase (DBH-Cre) with mice expressing floxed-targeting construct, which will result in the deletion of exon 22 and the subsequent loss of KIF1Bβ-isoform function [22].…”

MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression

“…Dynamin-Related Protein 1 (DRP1) is an upstream regulator of mitochondrial fission [13]. Several studies demonstrated that targeting DRP1 and mitochondrial fission may be an effective approach in cancer treatment [14]. Additionally, Fission, Mitochondrial 1 (FIS1), which serves as a receptor to recruit DRP1 to mitochondria, has also been uncovered to promote CDDP sensitivity in tongue squamous cell carcinoma [15].…”

KIF1Bβ and Neuroblastoma: Failure to Divide and Cull

“…In this issue of Developmental Cell , Li et al (2016) show that KIF1Bβ binding releases calcineurin autoinhibition, leading to dephosphorylation of the DRP1 GTPase and subsequent mitochondrial fragmentation. KIF1Bβ impairment causes mitochondrial hyperfusion, impairing developmental apoptosis and promoting tumorigenesis.…”

“…In this issue of Developmental Cell , Li et al (2016) provide an additional mechanism to explain the effects of KIF1Bβ on tumorigenesis. These authors found that KIF1Bβ activates the Ca 2+ -calmodulin-dependent protein phosphatase calcineurin by binding and stabilizing the calmodulin-calcineurin complex, relieving enzymatic autoinhibition (more completely than Ca 2+ alone) and permitting substrate recognition broadly.…”

“…This result is quite daunting upon initial consider-since calcineurin is a ubiquitous mediator of cellular responses to Ca 2+ signaling—with many substrates—and its dysregulation has already been implicated in a host of immune, neurodegenerative, and oncologic disorders. Importantly, out of the panoply of known calcineurin substrates, Li et al (2016) focused on a critical role for calcineurin-dependent activation of DRP1, a dynamin-related, multimeric GTPase that mediates mitochondrial fission, a critical event during apoptosis. The authors found that KIF1Bβ affects mitochondrial morphology through calcineurin-dependent dephosphorylation of DRP1 Ser637, which is phosphorylated by protein kinase A (PKA).…”