The Atypical Kinesin KIF26A Facilitates Termination of Nociceptive Responses by Sequestering Focal Adhesion Kinase

Kinesin superfamily proteins (KIFs) are molecular motors that typically alter the subcellular localization of their cargos. However, the atypical kinesin KIF26A does not serve as a motor but can bind microtubules and affect cellular signaling cascades. Here, we show that KIF26A maintains intracellular calcium homeostasis and negatively regulates nociceptive sensation. Kif26a−/− mice exhibit intense and prolonged nociceptive responses. In their primary sensory neurons, excessive inhibitory phosphorylation of plasma membrane Ca2+ ATPase (PMCA) mediated by focal adhesion kinase (FAK) rendered the Ca transients resistant to termination, and the peripheral axonal outgrowth was significantly enhanced. Upstream, KIF26A is directly associated with a FERM domain of FAK and antagonizes FAK function in integrin-Src family kinase (SFK)-FAK signaling, possibly through steric hindrance and localization to cytoplasmic microtubules. [Display omitted] •The nociceptive responses of Kif26a−/− mice are abnormally prolonged•Kif26a−/− DRG axons are hyperbranched, and their Ca transients are prolonged•KIF26A sequesters FAK on microtubules and increases Ca pump activity•The SFK inhibitor PP2 reverses Kif26a−/− phenotypes in vitro and in vivo Wang et al. establish a mouse model of pain by deleting the Kif26a gene, which encodes an atypical kinesin. The nociceptive response of this model is abnormally prolonged. KIF26A sequesters FAK onto cytoplasmic microtubules and facilitates Ca pump activity, which leads to prolonged pain response.