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

Abstract

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 Ca 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.

Neurexin and Frizzled intercept axonal-transport at microtubule minus-ends to control synapse formation

“…Complete loss of VAB-8 (as opposed the mere reduction that is observed in nrx-1 mutants) may trigger activation of the signal that locally disrupts PTRN-1 and NOCA-1. This interpretation is consistent with previously described roles for VAB-8 and KIF26 in regulating signaling pathways such as Netrin, Slit, FAK and GDNF (Wang et al, 2018; Zhou et al, 2009).…”

“…Kif26A functions in enteric and sensory neurons, where it regulates GDNF-Ret and FAK signaling, respectively. Kif26B regulates cell polarization and migration (Guillabert-Gourgues et al, 2016; Susman et al, 2017; Wang et al, 2018; Zhou et al, 2009) and mutations in human KIF26B are associated with progressive microcephaly and spinocerebellar ataxia (Nibbeling et al, 2017; Wojcik et al, 2018). In C. elegans , vab-8 is required for cell migration, axon extension of posteriorly growing neurons and GAP junction localization (Meng et al, 2016; Wightman et al, 1996; Wolf et al, 1998).…”

“…Precisely how VAB-8 promotes pauses of dynein remains to be elucidated. Kif26a was proposed to anchor and regulate kinase pathways on the microtubule lattice (Wang et al, 2018; Zhou et al, 2009), raising the possibility that VAB-8 at minus ends may localize a kinase that could phosphorylate dynein or its cargo. A potential candidate would be JNK, which is required for DCV capture and SVP clustering (Bharat et al, 2017; Wu et al, 2013).…”

‘Kinesinopathies’: emerging role of the kinesin family member genes in birth defects

“…3 KIF26A was suggested to play a role in enteric nervous system development, because knockout mice develop a megacolon and enteric nerve hypoplasia, 19 and to negatively regulate nociceptive sensation. 20 A significant number of KIFs play a prominent role in ciliogenesis and cilia function. They regulate cilia length, ciliary assembly/disassembly and can have motile cilia-specific functions.…”

Kinesins in Mammalian Spermatogenesis and Germ Cell Transport

“…KIF26A modulates FA and cell adhesion possibly via its effect on protein levels of FAK/p-FAK, E-cadherin/N-cadherin, and p-β-catenin in gastric cancer and mesenchymal cells. KIF26A has also been demonstrated to interact directly with FAK and to drive a pathway that inhibits integrin-SFK-FAK pathway signaling in primary cultured neurons and mouse brains ( Combes et al, 2015 ; Wang et al, 2018 ; Ma et al, 2021 ). KIF17 not only stabilizes microtubule, but also enhances cell-cell adhesions by boosting apical actin network assembly and junctional E-cadherin accumulation, and this activity is independent of microtubule binding in epithelial cells ( Acharya et al, 2016 ; Kreitzer and Myat, 2018 ).…”