Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0002440
UniProt IDQ9Y4G8
Primary gene name(s)RAPGEF2
Synonym gene name(s)KIAA0313, NRAPGEP, PDZGEF1
Protein nameRap guanine nucleotide exchange factor 2
Protein functionFunctions 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 locationCytoplasm. 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 codeClick here for more information.
Amino acid sequence
FASTA format: Q9Y4G8
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 interaction115045
Phylogenetic treeQ9Y4G8
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
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-0.4654941380888930.1564961988085470.251756933337861
AZA vs. DISU0.8127779835890430.001424916414991760.0952210209171597
AZA vs. IL70.08046224632720530.6772333480441710.999311006273513
AZA vs. SAHA0.5273005180352780.0317709399595630.206137541869254
DISU vs. CD31.264220219196380.0005904311565091410.00262696554109173
DISU vs. IL7-0.7409367142646040.003468077863352130.0602521520309614
DISU vs. SAHA-0.2838256207336940.3311188556116380.711743252323508
DMSO vs. AZA0.09272267117657310.5827756633339721
DMSO vs. CD30.5458049064933020.08907001269445350.155539555029783
DMSO vs. DISU-0.7221666963674480.003254650998868680.123035921460283
DMSO vs. IL7-0.004914256325792980.9783087780889710.996015724298726
DMSO vs. SAHA0.4276984121474180.07126457797369450.311493171299753
HIV vs. Mock in Activation-0.1341175857887520.8311944032900740.999983755607037
HIV vs. Mock in Latency-0.005470190111675850.9737375424690130.999834320637052
IL7 vs. CD30.5542648071793650.08577381175749010.167992290101436
SAHA vs. CD30.9671429632854650.006800275965191840.0185182795076691
SAHA vs. IL70.44249091030510.07120446049764370.232676357585407
(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
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
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)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
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
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
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)
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
6 h 24 h 48 h 72 h RTi
unknown unknown unknown unknown unknown
(2). Navare et al., Virology, 2012

SUP-T1 cell line
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
Affymetrix Prob ID Fold Change In CD8? Category
203097_s_at 1.4 No downregulated in CD8+ cells

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

not found

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

not found

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04010 MAPK signaling pathway - Homo sapiens (human)
hsa04015 Rap1 signaling pathway - Homo sapiens (human)
hsa04530 Tight junction - Homo sapiens (human)
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