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 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.
Highlights
Kinesin superfamily proteins (KIFs) are best characterized as molecular motors that can alter the subcellular localization of their cargos, but how this differential localization modulates the cargo function is still largely elusive (Hirokawa et al, 2009, 2010)
We have previously demonstrated that KIF26A negatively regulates receptor tyrosine-kinase (RTK)/Grb2 signal transduction to the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein (MAP) kinase (MAPK) cascades in enteric neurons and is essential for preventing the occurrence of megacolon (Zhou et al, 2009)
The sensitivity and morphological development of sensory neurons is known to be critically managed by extracellular matrix and integrin signaling (Alessandri-Haber et al, 2008; Dina et al, 2004; Fu et al, 2004), as well as by the growth factors and RTK signaling (Schaible, 2007) that is augmented by the axonal transport of the nerve growth factor (NGF) receptor TrkA by the kinesin-3 motor KIF1A (Tanaka et al, 2016)
Summary
Kinesin superfamily proteins (KIFs) are best characterized as molecular motors that can alter the subcellular localization of their cargos, but how this differential localization modulates the cargo function is still largely elusive (Hirokawa et al, 2009, 2010). The sensitivity and morphological development of sensory neurons is known to be critically managed by extracellular matrix and integrin signaling (Alessandri-Haber et al, 2008; Dina et al, 2004; Fu et al, 2004), as well as by the growth factors and RTK signaling (Schaible, 2007) that is augmented by the axonal transport of the nerve growth factor (NGF) receptor TrkA by the kinesin-3 motor KIF1A (Tanaka et al, 2016) These signaling pathways merge at the dynamic formation of the unique heterodimer kinase complex of Src family kinases (SFKs) and focal adhesion kinase (FAK), which are mutually activated by phosphorylation to transduce the signals to potentiate the following sensation mechanism (Calalb et al, 1995; Lietha et al, 2007): First, the SFK/FAK dual-kinase complex augments the Erk activity that facilitates axonal elongation and branching (Newbern et al, 2011; Paveliev et al, 2007). Because of the scarcity of genetic animal models available, investigations of the mechanistic link between integrin-mediated signaling and pain modulation are still in progress
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