The A2A Adenosine Receptor Rescues Neuritogenesis Impaired by p53 Blockage via KIF2A, a Kinesin Family Member

The A(2A) adenosine receptor (A(2A)R) is a G-protein coupled receptor. We previously reported that the C terminus of the A(2A)R binds to translin-associated protein X (TRAX) and modulates nerve growth factor (NGF)-evoked neurite outgrowth in PC12 cells. Herein, we show that neuritogenesis of primary hippocampal neurons requires p53 because blockage of p53 suppressed neurite outgrowth. The impaired neuritogenesis caused by p53 blockage was rescued by activation of the A(2A)R (designated the A(2A) rescue effect) in a TRAX-dependent manner. Importantly, suppression of a TRAX-interacting protein (kinesin heavy chain member 2A, KIF2A) inhibited the A(2A) rescue effect, whereas overexpression of KIF2A caused a rescue effect. Expression of a KIF2A fragment (KIF2A(514)), which disturbed the interaction between KIF2A and TRAX, blocked the rescue effect. Transient colocalization of TRAX and KIF2A was detected in the nucleus of PC12 cells upon NGF treatment. These data suggest that functional interaction between KIF2A and TRAX is critical for the A(2A) rescue effect. Moreover, p53 blockage during NGF treatment prevented the redistribution of KIF2A from the nucleus to the cytoplasmic region. Expression of a nuclear-retained KIF2A variant (NLS-KIF2A) did not rescue the impaired neurite outgrowth as did the wildtype KIF2A. Therefore, redistribution of KIF2A to the cytoplasmic fraction is a prerequisite for neurite outgrowth. Collectively, we demonstrate that KIF2A functions downstream of p53 to mediate neuritogenesis of primary hippocampal neurons and PC12 cells. Stimulation of the A(2A)R rescued neuritogenesis impaired by p53 blockage via an interaction between TRAX and KIF2A. (C) 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 604-621, 2010