| Annotated protein: | Ras-specific guanine nucleotide-releasing factor 1 (Ras-GRF1) (Guanine nucleotide-releasing protein) (GNRP) (P140 Ras-GRF). Gene symbol: RASGRF1. Taxonomy: Rattus norvegicus (Rat). Uniprot ID: P28818 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ RASGRF1 |
| Ontology domain: | Biological Process |
| SynGO term: | postsynaptic modulation of chemical synaptic transmission (GO:0099170) |
| Synapse type(s): | hippocampus, glutamatergic |
| Annotated paper: | Krapivinsky G, et al. "The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1" Neuron. 2003 Nov 13;40(4):775-84 PMID:14622581 |
| Figure(s): | Figure 1, 2, 3, 5 |
| Annotation description: | Figure 1, 2: NR2B (GRIN2B) and RasGRF1 (aka. GRF1, GNRP, CDC25) interact in vitro and in vivo. "Thus, truncation of the RasGRF1-specific sequence from either the C or N terminus resulted in loss of binding, suggesting that several separated protein segments may be responsible for specific interactions. Therefore, the RasGRF1 domain interacting with NR2B is localized between amino acids 714-913 of RasGRF1. The peptide encoding this region of RasGRF1 was designated as the RasGRF1-BD and used in subsequent experiments." Figure 3: Disruption of NR2B-RasGRF1 interaction abrogates NMDAR-dependent ERK1,2 activation. "Thus, expression of the dominant-negative form of RasGRF1, the complete BDs (but not overlapping peptides encoding only portions of the binding domains), effectively inhibited the NMDAR-dependent activation of ERK. These data support the hypothesis that a direct link between NR2B and RasGRF1 is critical for NMDAR-specific ERK activation." Figure 5: Blocking peptides RasGRF1-BD and NR2B-BD did not change the localization or density of NR2B or PSD95. Thus further supports the model proposed by authors where RasGRF1 directly interacts with NR2B at the postsynaptic membrane in order to activate ERK. authors summarise; "Suppression of NMDA-dependent ERK activation by the dominant-negative form of RasGRF1 suggests that RasGRF1 is a crucial intermediate between the NMDAR and ERK activation. The interaction between NR2B and RasGRF1, and our demonstration that disruption of this interaction attenuated NMDA-dependent ERK activation, strongly suggests that the NR2B subunit directly links the NMDAR to ERK activation. This finding, together with fact that both ERK (Adams and Sweatt, 2002) and RasGRF1 (Giese et al., 2001) are important for hippocampal-dependent memory, suggests that the NMDAR-RasGRF1-ERK signaling chain is integral to hippocampal memory formation." |
| Evidence tracking, Biological System: | Non-neuronal tissue Cultured neurons |
| Evidence tracking, Protein Targeting: | Antagonist / agonist Antibody (detection) |
| Evidence tracking, Experiment Assay: | IP + WB/MSMS Confocal |
| Annotator(s): | Frank Koopmans (ORCID:0000-0002-4973-5732) Guus Smit (ORCID:0000-0002-2286-1587) Matthijs Verhage (ORCID:0000-0002-2514-0216) |
| Lab: | Department of Functional Genomics, Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands |
| Additional literature: | "Ras-GRF1 mediates signaling from ifenprodil-sensitive (NR2B-containing) NMDARs to the Rac effector p38 MAP kinase, a promoter of LTD." @ PMID:16467520 "Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories." @ PMID:9384379 "Figure 2. Plk2 Induced by Overactivity Eliminates RasGRF1 and SPAR in Neurons" "Finally, we investigated whether Plk2 phosphorylation of Ras/Rap regulators is important for the PTX effects on surface AMPARs. As before, PTX stimulation reduced sGluA1/A2 levels in proximal dendrites (Figures 7I-7L). Overexpression of RasGRF1 WT or its phosphomutant (S71A) significantly increased sGluA1 expression, and the sGluA1 loss by PTX was partially blocked in neurons expressing S71A (Figures 7I and 7K). In contrast, RasGRF1 expression did not increase sGluA2 levels or prevent PTX-mediated removal of sGluA2 (Figures 7J and 7L), confirming the above result that silencing of RasGRF1 did not greatly reduce sGluA2 (Figures 7G and 7H)." @ PMID:21382555 "Phosphorylation of ERK1/2 in response to glutamate, dopamine D1 agonist, or both stimuli simultaneously is impaired in Ras-GRF1- deficient striatal cells and organotypic slices of the striatonigral MSN compartment. Consistently, behavioral responses to cocaine are also affected in mice deficient for Ras-GRF1 or overexpressing it." @ PMID:19446794 "NMDA receptor-dependent LTP induction robustly activated CaMKI, the Ca2+-stimulated Ras activator Ras-GRF1 (Ras-guanyl-nucleotide releasing factor), and ERK. STO-609 blocked the activation of all three enzymes during LTP without affecting basal synaptic transmission, activation of CaMKII, or cAMP-dependent activation of ERK." @ PMID:15689566 "Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway." @ PMID:20237287 |
| SynGO annotation ID: | 5461 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |