RGD Reference Report - Rap1GAP interacts with RET and suppresses GDNF-induced neurite outgrowth. - Rat Genome Database

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Rap1GAP interacts with RET and suppresses GDNF-induced neurite outgrowth.

Authors: Jiao, L  Zhang, Y  Hu, C  Wang, YG  Huang, A  He, C 
Citation: Jiao L, etal., Cell Res. 2011 Feb;21(2):327-37. doi: 10.1038/cr.2010.139. Epub 2010 Sep 28.
RGD ID: 9835042
Pubmed: PMID:20877310   (View Abstract at PubMed)
PMCID: PMC3193442   (View Article at PubMed Central)
DOI: DOI:10.1038/cr.2010.139   (Journal Full-text)

Glial cell line-derived neurotrophic factor (GDNF) was originally recognized for its ability to promote survival of midbrain dopaminergic neurons, but it has since been demonstrated to be crucial for the survival and differentiation of many neuronal subpopulations, including motor neurons, sympathetic neurons, sensory neurons and enteric neurons. To identify possible effectors or regulators of GDNF signaling, we performed a yeast two-hybrid screen using the intracellular domain of RET, the common signaling receptor of the GDNF family, as bait. Using this approach, we identified Rap1GAP, a GTPase-activating protein (GAP) for Rap1, as a novel RET-binding protein. Endogenous Rap1GAP co-immunoprecipitated with RET in neural tissues, and RET and Rap1GAP were co-expressed in dopaminergic neurons of the mesencephalon. In addition, overexpression of Rap1GAP attenuated GDNF-induced neurite outgrowth, whereas suppressing the expression of endogenous Rap1GAP by RNAi enhanced neurite outgrowth. Furthermore, using co-immunoprecipitation analyses, we found that the interaction between RET and Rap1GAP was enhanced following GDNF treatment. Mutagenesis analysis revealed that Tyr981 in the intracellular domain of RET was crucial for the interaction with Rap1GAP. Moreover, we found that Rap1GAP negatively regulated GNDF-induced ERK activation and neurite outgrowth. Taken together, our results suggest the involvement of a novel interaction of RET with Rap1GAP in the regulation of GDNF-mediated neurite outgrowth.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to glial cell derived neurotrophic factor  IDA 9835042 RGD 
negative regulation of neuron differentiation  IMP 9835042 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
axon  IDA 9835042; 9835042 RGD 
dendrite  IDA 9835042; 9835042 RGD 
early endosome  IDA 9835042; 9835042 RGD 
neuronal cell body  IDA 9835042; 9835042 RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding  IPIRet (Rattus norvegicus)9835042 RGD 
protein binding  IPIRap1gap (Rattus norvegicus)9835042 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rap1gap  (Rap1 GTPase-activating protein)
Ret  (ret proto-oncogene)


Additional Information