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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646206 | PMC |
| http://dx.doi.org/10.1074/jbc.M115.646901 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex.
Nat Commun
January 2025
Department of Molecular Biosciences, University of South Florida, 4202 E Fowler Ave, Tampa, FL, 33620, USA.
Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Gαβγ structures, these snapshots primarily capture the fully activated complex. Consequently, the functions of intermediate GPCR-G protein complexes remain elusive.
View Article and Find Full Text PDFAntigen receptor ITAMs provide tonic signaling by acting as guanine nucleotide exchange factors to directly activate R-RAS2.
Sci Signal
January 2025
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
The small GTPase R-RAS2 regulates homeostatic proliferation and survival of T and B lymphocytes and, when present in high amounts, drives the development of B cell chronic lymphocytic leukemia. In normal and leukemic lymphocytes, R-RAS2 constitutively binds to antigen receptors through their immunoreceptor tyrosine-based activation motifs (ITAMs) and promotes tonic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Here, we examined the molecular mechanisms underlying this direct interaction and its consequences for R-RAS2 activity.
View Article and Find Full Text PDFThe small GTPase MRAS is a broken switch.
Nat Commun
January 2025
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Intense research on founding members of the RAS superfamily has defined our understanding of these critical signalling proteins, leading to the premise that small GTPases function as molecular switches dependent on differential nucleotide loading. The closest homologs of H/K/NRAS are the three-member RRAS family, and interest in the MRAS GTPase as a regulator of MAPK activity has recently intensified. We show here that MRAS does not function as a classical switch and is unable to exchange GDP-to-GTP in solution or when tethered to a lipid bilayer.
View Article and Find Full Text PDFMultiomics analysis reveals the involvement of NET1 in tumour immune regulation and malignant progression.
Sci Rep
January 2025
Department of General Surgery, The Second Xiangya Hospital, Central South University, No. 139 People's Road, Changsha, 410011, Hunan, People's Republic of China.
Neuroepithelial cell transforming gene 1 (NET1) is a member of the Ras homologue family member A (RhoA) subfamily of guanine nucleotide exchange factors and a key protein involved in the activation of Rho guanosine triphosphatases, which act as regulators of cell proliferation, cytoskeletal organization, and cell movement and are crucial for cancer spread. Research has shown that NET1 can regulate the malignant biological functions of tumour cells, such as growth, invasion, and metastasis, and it is closely related to the progression of pancreatic cancer, gastric cancer, and liver cancer. However, the comprehensive role and mechanistic function of NET1 in other types of cancer remain largely unexplored.
View Article and Find Full Text PDFExcitable Ras dynamics-based screens reveal RasGEFX is required for macropinocytosis and random cell migration.
Nat Commun
January 2025
Laboratory of Single Molecule Biology, Graduate School of Science and Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Excitable systems of eukaryotic chemotaxis can generate asymmetric signals of Ras-GTP-enriched domains spontaneously to drive random cell migration without guidance cues. However, the molecules responsible for the spontaneous signal generation remain elusive. Here, we characterized RasGEFs encoded in Dictyostelium discoideum by live-cell imaging of the spatiotemporal dynamics of Ras-GTP and hierarchical clustering, finding that RasGEFX is primarily required for the spontaneous generation of Ras-GTP-enriched domains and is essential for random migration in combination with RasGEFB/M/U in starved cells, and they are dispensable for chemotaxis to chemoattractant cAMP.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!