title: MYCBP2 Is a Guanosine Exchange Factor for Ran Protein and Determines Its Localization in Neurons of Dorsal Root Ganglia.
abstract: The small GTPase Ran coordinates retrograde axonal transport in neurons, spindle assembly during mitosis, and the nucleo-cytoplasmic transport of mRNA. Its localization is tightly regulated by the GTPase-activating protein RanGAP1 and the nuclear guanosine exchange factor (GEF) RCC1. We show that loss of the neuronal E3 ubiquitin ligase MYCBP2 caused the up-regulation of Ran and RanGAP1 in dorsal root ganglia (DRG) under basal conditions and during inflammatory hyperalgesia. SUMOylated RanGAP1 physically interacted with MYCBP2 and inhibited its E3 ubiquitin ligase activity. Stimulation of neurons induced a RanGAP1-dependent translocation of MYCBP2 to the nucleus. In the nucleus of DRG neurons MYCBP2 co-localized with Ran and facilitated through its RCC1-like domain the GDP/GTP exchange of Ran. In accordance with the necessity of a GEF to promote GTP-binding and nuclear export of Ran, the nuclear localization of Ran was strongly increased in MYCBP2-deficient DRGs. The finding that other GEFs for Ran besides RCC1 exist gives new insights in the complexity of the regulation of the Ran signaling pathway.
authors: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, Frankfurt 60590, Germany.
authors: Angela
authors: A
authors: Dörr
authors: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, Frankfurt 60590, Germany.
authors: Sandra
authors: S
authors: Pierre
authors: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, Frankfurt 60590, Germany.
authors: Dong D
authors: DD
authors: Zhang
authors: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, Frankfurt 60590, Germany.
authors: Marina
authors: M
authors: Henke
authors: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, Frankfurt 60590, Germany.
authors: Sabrina
authors: S
authors: Holland
authors: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, Frankfurt 60590, Germany scholich@em.uni-frankfurt.de.
authors: Klaus
authors: K
authors: Scholich
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases; D020931:ran GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C102460:Ran protein, mouse; C532954:Mycbp2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D020931:ran GTP-Binding Protein
keywords: GTPase; GTPase activating protein (GAP); Mycbp2; Ran; RanGAP1; dorsal root ganglia; guanine nucleotide exchange factor (GEF); neuron