Activation of the A2A adenosine receptor modulates the role of kinesin Kif2A in the NGF‐mediated differentiation

Abstract

The A2A adenosine receptor (A2A‐R) has been implicated in modulating neuronal functions. We previously identified Translin associated protein X (TRAX) as an interacting protein of the A2A‐R. Via a TRAX‐dependent manner, activation of the A2A‐R rescued the NGF‐induced neurite outgrowth impaired by p53 inactivation in PC12. Overexpression of a TRAX‐interacting protein (kinesin Kif2A) also effectively rescued the damaged neurite outgrowth. Down‐regulation of Kif2A using short hairpin RNA (shRNA) further demonstrated its importance. Detailed analyses revealed that expression of Kif2A was elevated in the first 6 hr of NGF treatment, suggesting a critical role of Kif2A in the NGF‐induced differentiation. Blocking the p53‐mediated pathway during NGF‐treatment using p53 mutants or PFT‐ ?Ñ (1) suppressed the NGF‐induced Kif2A expression, (2) prevented the interaction between Kif2A and TRAX, and (3) retained Kif2A in the nucleus. Stimulation of the A2A‐R not only rescued the NGF‐induced neurite outgrowth damaged by p53 blockage, but also translocated Kif2A from the nucleus to the cytosol where the processes of neurite outgrowth occur. Collectively, the above findings suggest that Kif2A is a novel downstream target of p53, and that activation of the A2AR rescued the p53‐impaired neurite outgrowth through a functional interaction between TRAX and Kif2A.