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- Table of Contents
Facts about Rap guanine nucleotide exchange factor 2.
Shows poor activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844, PubMed:10548487, PubMed:11359771).
Human | |
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Gene Name: | RAPGEF2 |
Uniprot: | Q9Y4G8 |
Entrez: | 9693 |
Belongs to: |
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RAPGEF2 family |
CNrasGEF; KIAA0313; Neural RAP guanine nucleotide exchange protein; nRap GEP; NRAPGEP; PDZ domain containing guanine nucleotide exchange factor (GEF) 1; PDZGEF1; PDZ-GEF1PDZ domain-containing guanine nucleotide exchange factor 1; RA(Ras/Rap1A-associating)-GEF; RA-GEFDKFZP586O1422; Rap guanine nucleotide exchange factor (GEF) 2; rap guanine nucleotide exchange factor 2; Rap-GEP
Mass (kDA):
167.417 kDA
Human | |
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Location: | 4q32.1 |
Sequence: | 4; NC_000004.12 (159104051..159360173) |
Expressed in primary neuronal and endocrine cells (at protein level). Highest expression levels in brain. Lower expression levels in heart, kidney, lung, placenta and blood leukocytes.
Cytoplasm. Cytoplasm, perinuclear region. Cell membrane. Late endosome. Cell junction. Associated with the synaptic plasma membrane. Colocalizes with ADRB1 at the plasma membrane. Synaptosome. Enriched in synaptic plasma membrane and neuronal cell body. Colocalized with CTNNB1 at cell-cell contacts (By similarity). Localized diffusely in the cytoplasm before neuronal growth factor (NGF) stimulation. Recruited to late endosomes after NGF stimulation. Colocalized with the high affinity nerve growth factor receptor NTRK1 at late endosomes. Translocated to the perinuclear region in a RAP1A-depende
RAPGEF2 is a member of the RAS family and disrupts adherens junctions. This protein interacts with PSEN1 and CDh2, and cleaves CDh2. Understanding RAPGEF2 and its potential uses will help you develop the best treatment options for your patients. Using this gene marker is a great way to find out how the protein affects the human body.
RAPGEF2 is an important member of the RAS family of transcription factors that regulate cell growth and development. It binds to the RAP1A and RAP2B (179541) GTPases and induces the expression of reporter genes. The function of RAPGEF2 is not fully understood. However, it has been found to interact with beta-catenin. The human RAPGEF2 protein has been detected in cell lines of various tissues.
Moreover, studies of cKO mice have shown that RAPGEF2 deficiency is associated with schizophrenia. These mice exhibited a reduced seizure threshold and displayed severe apical surface adherence junction defects. These mice also exhibited severe defects in the brain and RGC development. Further studies are required to determine whether Rapgef2 is essential for normal brain development and function and whether it is a contributor to mental disorders such as schizophrenia.
Molecular structures of RAPGEF2 show that Rap1A and Rap1B exhibit different expression patterns in cell culture. Rap1A and Rap2 are expressed in COS-7 cells. Rap1A co-transfected with HA-PDZ-GEF1 and GST-RBD probes increased the activity of Rap1A and Rap1B but did not increase the activity of other Ras family small GTPases.
Mice lacking Rapgef2 exhibit reduced spatial memory and learning abilities. Rapgef2-cKO mice also display a reduced freezing response during cued and context testing. Mice lacking Rapgef6 showed no deficiency in the Barnes circular maze test. This gene is a member of the RAS subfamily and is essential for the proper development of many mammals.
In humans, a mutation in Rapgef4 causes autism. Mice lacking Rapgef4 have severe spatial learning and social interaction defects. Similarly, a deletion of Rapgef1 impairs neuritogenesis. Rapgef2 also known as C3G is responsible for activating Rap1 downstream of Reelin signaling. It plays a crucial role in neural development and migration.
The role of Rapgef2 in the pathogenesis of Alzheimer's disease is unclear. In addition to its role in synaptopathy, RAPGEF2 is also involved in epilepsy. RAPGEF2 is involved in the activity-dependent remodeling of synapses. Further, RAPGEF2 may contribute to the pathogenesis of epilepsy by regulating higher brain functions.
Rapgef2 is a small GTPase that is important for maintaining adhesion junctures (AJs). AJs are crucial for proper development of neural progenitor cells and have a role in cerebellar neocortex development. The AJs are regulated by several factors, including Rapgef2 and Rap1.
Moreover, the deletion of Rapgef6 impairs both contextual and cued fear conditioning in mice. Although the deletion did not affect hippocampal and prefrontal cortex-dependent cognitive functions, Rapgef6 mice were significantly slower to freeze in the original context and showed a reduced anxiety-like behavior. Furthermore, Rapgef6 mice were less likely to freeze in novel contexts, but this effect was not significant at post-hoc comparisons.
Furthermore, loss of Rap1 impairs cellular motility through its role in regulating adhesion. In addition to its role in cell motility, Rap1 also has additional roles in junctional protein localization and balanced apical constriction. Consequently, the two proteins have distinct functions and may be regulated in parallel. However, this effect is not yet clear. The roles of Rap1 and Rap2 in adhesion formation remain unclear.
In addition, human genetic studies have shown a strong genetic association between Rapgef2 and schizophrenia. Rapgef2-cKO mice have abnormally formed ECM and display symptoms of mental retardation and epilepsy in addition to malformations of the commissural system and agenesis of corpus callosum (CC). Moreover, these mice have DISC-1 gene mutations.
Although the basal synaptic transmission is normal in Rapgef6-KO mice, the paired-pulse facilitation test failed to detect any changes in Rapgef2 genotype. However, Rapgef6-cKO mice showed mild behavioral abnormalities such as depression-like behavior in the Porsolt forced swim test and impaired working memory in T-maze tests. However, these results suggest that Rapgef2 and Rapgef6 play the same biochemical roles.
In addition to its role in LEC stability, Rapgef2 disruption also causes LECs to deteriorate in quality. Mice expressing Rapgef2 exhibited decreased permeability and increased normalized permeability in PKI-treated LECs, indicating that Rap1 plays a supporting role in AM signaling. The findings indicate that Rap1 contributes to adhesion stabilization by regulating the production of cell junctions in the adhesions.
In the human brain, RAPGEF2 is a member of the E-cadherin/catenin adhesion complex. Its components include E-cadherin/CDh2 and beta-catenin/JUP. Both catenins are found at adherens junctions. During neurodegeneration, these proteins interact with other components of the E-cadherin/catenin complex.
Moreover, RAPGEF2 has two downstream effectors, Rap1 and Rap2. They share 60% sequence homology, but exert different functions. Both regulate the removal of AMPA-type glutamate receptors from synapses. Rap2 causes the loss of excitatory synapses in neuronal synapses, whereas Rap1 has no effect on the morphology of spinner neurons.
Pathogenic variants of both genes were analyzed with the Chi-square test and the SPSS 20.0 statistical program. Moreover, differences between the transmembrane domain of APP and non-transmembrane domain of PSEN1 and PSEN2 were compared by Fisher test. Hence, the results of these studies are not definitive. The authors thank the authors for sharing their research findings.
The expression of RAPGEF2 was detected in all tissues and was called PDZGEF1 by de Rooij et al. Cell lines derived from different tissues expressed a PDZGEF1 protein of 200 kD. They also detected the RAS exchange motif between the RCBD domain and the PDZ domain. These results suggest that RAPGEF2 interacts with PSEN1.
The protein RAPGEF2 is a member of the cadherin superfamily. It preferentially interacts with its own counterparts when connecting cells. This interaction may also contribute to sorting heterogeneous cell types. It is involved in cell-cell adhesion and mobility mechanisms, as well as the proliferation of epithelial cells. CDh2 also binds integrin alpha-E/beta-7 and inhibits the production of APP C99 and C83. In addition, CDh2 serves as a receptor for Listeria monocytogenes.
To determine whether RAPGEF2 is targeted for degradation by SCF bTrCP, HEK293T cells were transfected with various proteins. Specifically, RAPGEF2, Skp1, Cul1, Rbx1, and Cul1 were expressed in HEK293T cells. bTrCP1 was tagged with FLAG or a DF-box to facilitate in vitro ubiquitylation of RAPGEF2. Immunoprecipitated RAPGEF2 was detected by immunoprecipitating with anti-FLAG resin and anti-RAPGEF2 antibody.
PMID: 10548487 by Ohtsuka T., et al. nRap GEP: a novel neural GDP/GTP exchange protein for rap1 small G protein that interacts with synaptic scaffolding molecule (S-SCAM).
PMID: 10608844 by Liao Y., et al. RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a Ras/Rap1A-associating domain, is conserved between nematode and humans.