title: RabGEF1/Rabex-5 Regulates TrkA-Mediated Neurite Outgrowth and NMDA-Induced Signaling Activation in NGF-Differentiated PC12 Cells.
abstract: Nerve growth factor (NGF) binds to its cognate receptor TrkA and induces neuronal differentiation by activating distinct downstream signal transduction events. RabGEF1 (also known as Rabex-5) is a guanine nucleotide exchange factor for Rab5, which regulates early endosome fusion and vesicular trafficking in endocytic pathways. Here, we used the antisense (AS) expression approach to induce an NGF-dependent sustained knockdown of RabGEF1 protein expression in stable PC12 transfectants. We show that RabGEF1 is a negative regulator of NGF-induced neurite outgrowth and modulates other cellular and signaling processes that are activated by the interaction of NGF with TrkA receptors, such as cell cycle progression, cessation of proliferation, and activation of NGF-mediated downstream signaling responses. Moreover, RabGEF1 can bind to Rac1, and the activation of Rac1 upon NGF treatment is significantly enhanced in AS transfectants, suggesting that RabGEF1 is a negative regulator of NGF-induced Rac1 activation in PC12 cells. Furthermore, we show that RabGEF1 can also interact with NMDA receptors by binding to the NR2B subunit and its associated binding partner SynGAP, and negatively regulates activation of nitric oxide synthase activity induced by NMDA receptor stimulation in NGF-differentiated PC12 cells. Our data suggest that RabGEF1 is a negative regulator of TrkA-dependent neuronal differentiation and of NMDA receptor-mediated signaling activation in NGF-differentiated PC12 cells.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: See-Ying
authors.initials: SY
authors.lastname: Tam
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Lilla
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Janet
authors.initials: J
authors.lastname: Kalesnikoff
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Mindy
authors.initials: M
authors.lastname: Tsai
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis* / Q000235:genetics; D016202:N-Methylaspartate / Q000008:administration & dosage; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C000608449:RABGEF1 protein, rat; D016202:N-Methylaspartate; D020932:Nerve Growth Factor; D020917:Receptor, trkA