周 如贇

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.

The kinesin superfamily proteins (KIFs) are motor proteins that transport organelles and protein complexes in a microtubule- and ATP-dependent manner. We identified KIF26A as a new member of the murine KIFs. KIF26A is a rather atypical member as it lacks ATPase activity. Mice with a homozygous deletion of Kif26a developed a megacolon with enteric nerve hyperplasia. Kif26a(-/-) enteric neurons showed hypersensitivity for GDNF-Ret signaling, and we find that KIF26A suppressed GDNF-Ret signaling by direct binding and inhibition of Grb2, an essential component of GDNF/Akt/ERK signaling. We therefore propose that the unconventional kinesin KIF26A plays a key role in enteric nervous system development by repressing a cell growth signaling pathway.