RGD Reference Report - A functional dynein-microtubule network is required for NGF signaling through the Rap1/MAPK pathway. - Rat Genome Database

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A functional dynein-microtubule network is required for NGF signaling through the Rap1/MAPK pathway.

Authors: Wu, C  Ramirez, A  Cui, B  Ding, J  Delcroix, JD  Valletta, JS  Liu, JJ  Yang, Y  Chu, S  Mobley, WC 
Citation: Wu C, etal., Traffic. 2007 Nov;8(11):1503-20. Epub 2007 Sep 6.
RGD ID: 10040965
Pubmed: PMID:17822405   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1600-0854.2007.00636.x   (Journal Full-text)

Rap1 transduces nerve growth factor (NGF)/tyrosine receptor kinase A (TrkA) signaling in early endosomes, leading to sustained activation of the p44/p42 mitogen-activated protein kinases (MAPK1/2). However, the mechanisms by which NGF, TrkA and Rap1 are trafficked to early endosomes are poorly defined. We investigated trafficking and signaling of NGF, TrkA and Rap1 in PC12 cells and in cultured rat dorsal root ganglion (DRG) neurons. Herein, we show a role for both microtubule- and dynein-based transport in NGF signaling through MAPK1/2. NGF treatment resulted in trafficking of NGF, TrkA and Rap1 to early endosomes in the perinuclear region of PC12 cells where sustained activation of MAPK1/2 was observed. Disruption of microtubules with nocodazole in PC12 cells had no effect on the activation of TrkA and Ras. However, it disrupted intracellular trafficking of TrkA and Rap1. Moreover, NGF-induced activation of Rap1 and sustained activation of MAPK1/2 were markedly suppressed. Inhibition of dynein activity through overexpression of dynamitin (p50) blocked trafficking of Rap1 and the sustained phase of MAPK1/2 activation in PC12 cells. Remarkably, even in the continued presence of NGF, mature DRG neurons that overexpressed p50 became atrophic and most (>80%) developing DRG neurons died. Dynein- and microtubule-based transport is thus necessary for TrkA signaling to Rap1 and MAPK1/2.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to nerve growth factor stimulus  IEP 10040965 RGD 
response to antineoplastic agent  IDA 10040965nocodazoleRGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
early endosome  IDA 10040965 RGD 
perinuclear region of cytoplasm  IDA 10040965 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rap1a  (RAP1A, member of RAS oncogene family)


Additional Information