title: Ectopic expression of H2AX protein promotes TrkA-induced cell death via modulation of TrkA tyrosine-490 phosphorylation and JNK activity upon DNA damage.
abstract: We previously reported that TrkA overexpression causes accumulation of γH2AX proteins in the cytoplasm, subsequently leading to massive cell death in U2OS cells. To further investigate how cytoplasmic H2AX is associated with TrkA-induced cell death, we established TrkA-inducible cells stably expressing GFP-tagged H2AX. We found that TrkA co-localizes with ectopically expressed GFP-H2AX proteins in the cytoplasm, especially at the juxta-nuclear membranes, which supports our previous results about a functional connection between TrkA and γH2AX in TrkA-induced cell death. γH2AX production from GFP-H2AX proteins was significantly increased when TrkA was overexpressed. Moreover, ectopic expression of H2AX activated TrkA-mediated signal pathways via up-regulation of TrkA tyrosine-490 phosphorylation. In addition, suppression of TrkA tyrosine-490 phosphorylation under a certain condition was removed by ectopic expression of H2AX, indicating a functional role of H2AX in the maintenance of TrkA activity. Indeed, TrkA-induced cell death was highly elevated by ectopic H2AX expression, and it was further accelerated by DNA damage via JNK activation. These all results suggest that cytoplasmic H2AX could play an important role in TrkA-mediated cell death by modulating TrkA upon DNA damage.
authors.affiliation: Department of Biochemistry and Institute of Health Sciences, Gyeongsang National University, School of Medicine, 92 Chilam-dong, JinJu 660-751, Republic of Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Jung
authors.forename: Deok Ryong
authors.initials: DR
authors.lastname: Kim
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D006657:Histones / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D010766:Phosphorylation; D020917:Receptor, trkA / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D014443:Tyrosine; D020917:Receptor, trkA; D048670:MAP Kinase Kinase 4