ArticleThe Journal of biological chemistry2013
Rab7 mutants associated with Charcot-Marie-Tooth disease cause delayed growth factor receptor transport and altered endosomal and nuclear signaling.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 55 citations in OpenAlex.
- Trial
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- Maspardin/SPG21 controls lysosome motility and TFEB phosphorylation through RAB7 positioning.The Journal of cell biology · 2026Article
- TRIM2 E3 ligase substrate discovery reveals zinc-mediated regulation of TMEM106B in the endolysosomal pathway.EMBO reports · 2026Article
- Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.Aging and disease · 2025Review
- VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.Expert opinion on therapeutic targets · 2024Review
- Rab7-dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis.eLife · 2024Article
- Peripheral Neuropathy and Decreased Locomotion of aExperimental neurobiology · 2023Article
- Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot-Marie-Tooth 2B Disease.Biomolecules · 2023Review
- Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.Cell death discovery · 2023Article
- CLUSTER guide RNAs enable precise and efficient RNA editing with endogenous ADAR enzymes in vivo.Nature biotechnology · 2022Article
- Programmed cell death 4 modulates lysosomal function by inhibiting TFEB translation.Cell death and differentiation · 2021Article
- Alteration of the late endocytic pathway in Charcot-Marie-Tooth type 2B disease.Cellular and molecular life sciences : CMLS · 2021Article
- Held Up in Traffic-Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease.Frontiers in molecular neuroscience · 2021Review
- Article
- Lysosomes as dynamic regulators of cell and organismal homeostasis.Nature reviews. Molecular cell biology · 2020Review
- Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases.Frontiers in molecular neuroscience · 2020Article
- A Model of Hereditary Sensory and Autonomic Neuropathy Type 1 Reveals a Role of Glycosphingolipids in Neuronal Polarity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Rab7 belongs to the Ras superfamily of small GTPases and is a master regulator of early to late endocytic membrane transport. Four missense mutations in the late endosomal Rab7 GTPase (L129F, K157N, N161T, and V162M) cause the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth type 2B (CMT2B) disease. As yet, the pathological mechanisms connecting mutant Rab7 protein expression to altered neuronal function are undefined. Here, we analyze the effects of Rab7 CMT2B mutants on epidermal growth factor (EGF)-dependent intracellular signaling and trafficking. Three different cell lines expressing Rab7 CMT2B mutants and stimulated with EGF exhibited delayed trafficking of EGF to LAMP1-positive late endosomes and lysosomes and slowed EGF receptor (EGFR) degradation. Expression of all Rab7 CMT2B mutants altered the Rab7 activation cycle, leading to enhanced and prolonged EGFR signaling as well as variable increases in p38 and ERK1/2 activation. However, due to reduced nuclear translocation of p38 and ERK1/2, the downstream nuclear activation of Elk-1 was decreased along with the expression of immediate early genes like c-fos and Egr-1 by the disease mutants. In conclusion, our results demonstrate that Rab7 CMT2B mutants impair growth factor receptor trafficking and, in turn, alter p38 and ERK1/2 signaling from perinuclear, clustered signaling endosomes. The resulting down-regulation of EGFR-dependent nuclear transcription that is crucial for normal axon outgrowth and peripheral innervation offers a crucial new mechanistic insight into disease pathogenesis that is relevant to other neurodegenerative diseases.
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