title: Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit enhanced NGF-stimulated signaling.
abstract: Missense mutants in the late endosomal Rab7 GTPase cause the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth disease type 2B (CMT2B). As yet, the pathological mechanisms connecting mutant Rab7 protein expression to altered neuronal function are undefined. Here, we analyze the effects Rab7 CMT2B mutants on nerve growth factor (NGF) dependent intracellular signaling in PC12 cells. The nerve growth factor receptor TrkA interacted similarly with Rab7 wild-type and CMT2B mutant proteins, but the mutant proteins significantly enhanced TrkA phosphorylation in response to brief NGF stimulation. Two downstream signaling pathways (Erk1/2 and Akt) that are directly activated in response to phospho-TrkA were differentially affected. Akt signaling, arising in response to activated TrkA at the plasma membrane was unaffected. However Erk1/2 phosphorylation, triggered on signaling endosomes, was increased. Cytoplasmic phospho-Erk1/2 persisted at elevated levels relative to control samples for up to 24 h following NGF stimulation. Nuclear shuttling of phospho Erk1/2, which is required to induce MAPK phosphatase expression and down regulate signaling, was greatly reduced by the Rab7 CMT2B mutants and explains the previously reported inhibition in PC12 neurite outgrowth. In conclusion, the data demonstrate a mechanistic link between Rab7 CMT2B mutants and altered TrkA and Erk1/2 signaling from endosomes.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Soumik
authors.initials: S
authors.lastname: BasuRay
authors.forename: Sanchita
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Elsa
authors.initials: E
authors.lastname: Romero
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wilson
authors.forename: Angela
authors.initials: A
authors.lastname: Wandinger-Ness
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D011992:Endosomes / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000090802:rab7 GTP-Binding Proteins; C000716466:rab7 GTP-binding proteins, rat; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020691:rab GTP-Binding Proteins