KIF1Bβ and Neuroblastoma: Failure to Divide and Cull

Abstract

Neuroblastomas are associated with KIF1Bβ mutations within tumor suppressor region 1p36. 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.

Figure 1. Model of KIF1Bβ-Dependent Effects on Mitochondrial Fission/Fusion Balance in NGF-Limiting Conditions

KIF1Bβ activates calcineurin (CN) by relieving autoinhibition, resulting in dephosphorylation of DRP1 Ser637. This triggers DRP1 translocation to mitochondria and subsequent division, leading to cytochrome c release (stars), apoptosis, and cell death. In the absence of KIF1Bβ, DRP1 Ser637 is phosphorylated (P) by PKA and remains modified. Mitochondrial fission is impaired, resulting in mitochondrial hyperfusion, aberrant cell survival, and promotion of tumorigenesis. Figure adapted from Anderson and Blackstone (2013).