Protein Information (annotations from UniProt)
| Database ID | HIV0002440 |
| UniProt ID | Q9Y4G8 |
| Primary gene name(s) | RAPGEF2 |
| Synonym gene name(s) | KIAA0313, NRAPGEP, PDZGEF1 |
| Protein name | Rap guanine nucleotide exchange factor 2 |
| Protein function | Functions as a guanine nucleotide exchange factor, GEF, which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Acts also as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP, PubMed:23800469, PubMed:10801446 or not, PubMed:10608844, PubMed:10548487, PubMed:11359771. Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s-alpha signaling pathway. Involved in the cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Provides also inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor, NGF-induced sustained activation of Rap1 at late endosomes and in brain-derived neurotrophic factor, BDNF-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions. {ECO:0000269|PubMed:10548487, ECO:0000269|PubMed:10608844, ECO:0000269|PubMed:10608883, ECO:0000269|PubMed:10801446, ECO:0000269|PubMed:10934204, ECO:0000269|PubMed:11359771, ECO:0000269|PubMed:12391161, ECO:0000269|PubMed:16272156, ECO:0000269|PubMed:17724123, ECO:0000269|PubMed:21840392, ECO:0000269|PubMed:23800469}. |
| Subcellular location | Cytoplasm. Cytoplasm, perinuclear region. Cell membrane. Late endosome. Cell junction {ECO:0000250}. Note=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-dependent manner. Translocated to the cell membrane. {ECO:0000250}. |
| ECO code | Click here for more information. |
| Amino acid sequence FASTA format: Q9Y4G8 |
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| Gene Ontology (Biological Process) Complete annatation | adenylate cyclase-activating adrenergic receptor signaling pathway [GO:0071880]; blood vessel development [GO:0001568]; brain-derived neurotrophic factor receptor signaling pathway [GO:0031547]; cAMP-mediated signaling [GO:0019933]; cellular response to cAMP [GO:0071320]; cellular response to cGMP [GO:0071321]; cellular response to nerve growth factor stimulus [GO:1990090]; establishment of endothelial barrier [GO:0061028]; establishment of endothelial intestinal barrier [GO:0090557]; forebrain neuron development [GO:0021884]; G-protein coupled receptor signaling pathway [GO:0007186]; intracellular signal transduction [GO:0035556]; MAPK cascade [GO:0000165]; microvillus assembly [GO:0030033]; negative regulation of cell proliferation [GO:0008285]; negative regulation of dendrite morphogenesis [GO:0050774]; negative regulation of melanin biosynthetic process [GO:0048022]; nerve growth factor signaling pathway [GO:0038180]; neuron migration [GO:0001764]; neuron projection development [GO:0031175]; neuropeptide signaling pathway [GO:0007218]; positive regulation of cAMP-dependent protein kinase activity [GO:2000481]; positive regulation of cAMP-mediated signaling [GO:0043950]; positive regulation of dendritic cell apoptotic process [GO:2000670]; positive regulation of ERK1 and ERK2 cascade [GO:0070374]; positive regulation of GTPase activity [GO:0043547]; positive regulation of neuron migration [GO:2001224]; positive regulation of neuron projection development [GO:0010976]; positive regulation of protein binding [GO:0032092]; positive regulation of protein kinase activity [GO:0045860]; positive regulation of vasculogenesis [GO:2001214]; protein localization to plasma membrane [GO:0072659]; Rap protein signal transduction [GO:0032486]; regulation of cell junction assembly [GO:1901888]; regulation of synaptic plasticity [GO:0048167]; small GTPase mediated signal transduction [GO:0007264]; ventricular system development [GO:0021591] |
| Gene Ontology (Molecular Function) Complete annatation | beta-1 adrenergic receptor binding [GO:0031697]; calcium ion binding [GO:0005509]; cAMP binding [GO:0030552]; diacylglycerol binding [GO:0019992]; GTPase activator activity [GO:0005096]; PDZ domain binding [GO:0030165]; phosphatidic acid binding [GO:0070300]; Rap guanyl-nucleotide exchange factor activity [GO:0017034]; Ras guanyl-nucleotide exchange factor activity [GO:0005088]; signal transducer activity [GO:0004871]; WW domain binding [GO:0050699] |
| Gene Ontology (Cellular Component) Complete annatation | apical plasma membrane [GO:0016324]; bicellular tight junction [GO:0005923]; cell-cell junction [GO:0005911]; cytoplasm [GO:0005737]; cytosol [GO:0005829]; endocytic vesicle [GO:0030139]; integral component of plasma membrane [GO:0005887]; late endosome [GO:0005770]; membrane [GO:0016020]; neuronal cell body [GO:0043025]; neuron projection [GO:0043005]; perinuclear region of cytoplasm [GO:0048471]; plasma membrane [GO:0005886]; protein complex [GO:0043234]; synapse [GO:0045202] |
| Protein-protein interaction | 115045 |
| Phylogenetic tree | Q9Y4G8 |
| HIV replication factor status |
Zhou et al., Cell. Host. Microbe., 2008 unknown Brass et al., Science, 2008 unknown Smith et al., J. Immunol, 2010 unknown |
| Interferon-stimulated gene status |
Lu et al., J. Virol., 2011 Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown; Schoggins JW and Rice CM, Curr. Opin. Virol., 2011 Targeted viruses: unknown Viral life cycle: unknown Mechanism related to antiviral activity: unknown |
| Anti-viral restriction factor |
Liu et al., Retrovirology, 2011 unknown (Triplicates) |
Gene Expression Profile top
Up-regulated; 
Down-regulated
For brief introduction to each study, please go to the help page.
Gene expression during HIV latency
| (1). Mohammadi et al., PLoS Pathog., 2014 Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model DMSO: Dimethyl suloxyde (negative control) - 0.0033% final SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies IL7: Interleukin-7 based stimulation DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM |
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| Experimental Condition | Log2 Fold Change | P value | Adjusted P value |
| AZA vs. CD3 | -0.465494138088893 | 0.156496198808547 | 0.251756933337861 |
| AZA vs. DISU | 0.812777983589043 | 0.00142491641499176 | 0.0952210209171597 |
| AZA vs. IL7 | 0.0804622463272053 | 0.677233348044171 | 0.999311006273513 |
| AZA vs. SAHA | 0.527300518035278 | 0.031770939959563 | 0.206137541869254 |
| DISU vs. CD3 | 1.26422021919638 | 0.000590431156509141 | 0.00262696554109173 |
| DISU vs. IL7 | -0.740936714264604 | 0.00346807786335213 | 0.0602521520309614 |
| DISU vs. SAHA | -0.283825620733694 | 0.331118855611638 | 0.711743252323508 |
| DMSO vs. AZA | 0.0927226711765731 | 0.582775663333972 | 1 |
| DMSO vs. CD3 | 0.545804906493302 | 0.0890700126944535 | 0.155539555029783 |
| DMSO vs. DISU | -0.722166696367448 | 0.00325465099886868 | 0.123035921460283 |
| DMSO vs. IL7 | -0.00491425632579298 | 0.978308778088971 | 0.996015724298726 |
| DMSO vs. SAHA | 0.427698412147418 | 0.0712645779736945 | 0.311493171299753 |
| HIV vs. Mock in Activation | -0.134117585788752 | 0.831194403290074 | 0.999983755607037 |
| HIV vs. Mock in Latency | -0.00547019011167585 | 0.973737542469013 | 0.999834320637052 |
| IL7 vs. CD3 | 0.554264807179365 | 0.0857738117574901 | 0.167992290101436 |
| SAHA vs. CD3 | 0.967142963285465 | 0.00680027596519184 | 0.0185182795076691 |
| SAHA vs. IL7 | 0.4424909103051 | 0.0712044604976437 | 0.232676357585407 |
| (2). Iglesias-Ussel et al., J. Virol., 2013 Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model |
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| Log2 Fold Change | P Value | ||
| unknown | unknown | ||
Gene expression during HIV infection and replication
| (1). Imbeault et al., PloS Pathog., 2012 Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells |
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| Experiment type | Log2 Fold Change | P Value | Adjusted P Value | ||
| Infected vs. Mock | unknown | unknown | unknown | ||
| Infected vs. Bystander | unknown | unknown | unknown | ||
| (2). Lefebvre et al., J. Virol., 2011 Transcriptome analysis of T-cell line (Sup T1) |
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| Log2 Fold Change | unknown | ||||
| (3). Li et al., J. Immunol., 2013 Lymphatic tissue |
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| Acute Fold Change | Acute P Value | Asymt Fold Change | Asypt P Value | AIDS Fold Change | AIDS P Value |
| unknown | unknown | unknown | unknown | unknown | unknown |
| (4). Chang et al., MBio., 2011 Transcriptome analysis of T-cell line (Sup T1) Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation |
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| Up-regulated (True) | TRUE | ||||
| (5). Sherrill-Mix et al., BMC Retrovirol., 2015 Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based |
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| Test Status | Log2 Fold Change | P Value | |||
| OK | 0.171111 | 0.264932 | |||
| (6). Rotger et al., PLoS Pathog., 2010 Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient (Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach) |
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| Log2 Fold Change | P Value | ||||
| unknown | unknown | ||||
Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV
| (1). Greenwood et al., Elife, 2016 Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset |
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| 6 h | 24 h | 48 h | 72 h | RTi | ||
| unknown | unknown | unknown | unknown | unknown | ||
| (2). Navare et al., Virology, 2012 SUP-T1 cell line |
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| FC-4hpi | P-value | FC-8hpi | P-value | FC-20hpi | P-value | Category |
| unknown | unknown | unknown | unknown | unknown | unknown | unknown |
| (3). Hyrcza et al., J. Virolo., 2007 Primary human CD4+ and CD8+ T Cells |
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| Affymetrix Prob ID | Fold Change | In CD8? | Category | |||
| 203097_s_at | 1.4 | No | downregulated in CD8+ cells | |||