title: The A2A adenosine receptor rescues neuritogenesis impaired by p53 blockage via KIF2A, a kinesin family member.
abstract: The A2A adenosine receptor (A2AR) is a G-protein-coupled receptor. We previously reported that the C terminus of the A2AR 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 A2AR (designated the A2A rescue effect) in a TRAX-dependent manner. Importantly, suppression of a TRAX-interacting protein (kinesin heavy chain member 2A, KIF2A) inhibited the A2A rescue effect, whereas overexpression of KIF2A caused a rescue effect. Expression of a KIF2A fragment (KIF2A514), 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 A2A 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 wild-type 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 A2AR rescued neuritogenesis impaired by p53 blockage via an interaction between TRAX and KIF2A.
authors.affiliation: Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chung-Nan
authors.initials: CN
authors.lastname: Sun
authors.forename: Hsiu-Chun
authors.initials: HC
authors.lastname: Chuang
authors.forename: Jiz-Yuh
authors.initials: JY
authors.lastname: Wang
authors.forename: Si-Ying
authors.initials: SY
authors.lastname: Chen
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Cheng
authors.forename: Chien-Fei
authors.initials: CF
authors.lastname: Lee
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000502:physiology*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D043705:Receptor, Adenosine A2A; D012097:Repressor Proteins; C498306:Tsnax protein, mouse; C498307:Tsnax protein, rat; D016159:Tumor Suppressor Protein p53; D020932:Nerve Growth Factor; C477238:KIF2A protein, mouse; D016547:Kinesins