Q8VCC8
SS
Gene name |
Rapgef3 (Epac, Epac1) |
Protein name |
Rap guanine nucleotide exchange factor 3 |
Names |
Exchange factor directly activated by cAMP 1 , Exchange protein directly activated by cAMP 1 , EPAC 1 , cAMP-regulated guanine nucleotide exchange factor I , cAMP-GEFI |
Species |
Mus musculus (Mouse) |
KEGG Pathway |
mmu:223864 |
EC number |
|
Protein Class |
|
Descriptions
Epac1 (RAPGEF3) is a guanine nucleotide exchange factor (GEF) for the small G protein Rap and is directly activated by cyclic AMP (cAMP). Epac1 contains a regulatory region with a cAMP-binding domain (CBD), a Dishev-elled, Egl-10, Pleckstrin (DEP) domain, and a catalytic region for GEF activity. Upon cAMP binding, Epac1 undergoes a conformational change that allows the interaction of its GEF domain with Rap, resulting in Rap activation and subsequent downstream effects, including integrin-mediated cell adhesion and cell-cell junction formation. cAMP also induces the translocation of Epac1 toward the plasma membrane (PM), which is requisite for cAMP-induced Rap activation at the PM and enhances Rap-mediated cell adhesion. In the autoinhibited state, the catalytic site is sterically covered by the N-terminal regulatory region, which occludes the Rap binding site. The autoinhibition is released by a conformational change induced by the binding of cAMP.
Autoinhibitory domains (AIDs)
Target domain |
661-918 (GEF catalytic domain) |
Relief mechanism |
Ligand binding |
Assay |
|
Accessory elements
No accessory elements
References
- Selvaratnam R et al. (2012) "The auto-inhibitory role of the EPAC hinge helix as mapped by NMR", PloS one, 7, e48707
- Ponsioen B et al. (2009) "Direct spatial control of Epac1 by cyclic AMP", Molecular and cellular biology, 29, 2521-31
- Gloerich M et al. (2010) "Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins", Molecular and cellular biology, 30, 5421-31
Autoinhibited structure
Activated structure
1 structures for Q8VCC8
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-Q8VCC8-F1 | Predicted | AlphaFoldDB |
74 variants for Q8VCC8
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs3389380066 | 19 | E>D | No | EVA | |
| rs220785121 | 22 | A>T | No | EVA | |
| rs3389388124 | 23 | V>M | No | EVA | |
| rs32264845 | 26 | P>S | No | EVA | |
| rs3389383780 | 29 | G>S | No | EVA | |
| rs3389347342 | 32 | P>A | No | EVA | |
| rs3389388180 | 32 | P>R | No | EVA | |
| rs3389392876 | 51 | P>S | No | EVA | |
| rs3405959845 | 64 | R>L | No | EVA | |
| rs49134673 | 67 | C>* | No | EVA | |
| rs3406455022 | 67 | C>G | No | EVA | |
| rs3406686508 | 68 | I>T | No | EVA | |
| rs3406477762 | 68 | I>V | No | EVA | |
| rs3405959844 | 69 | Q>H | No | EVA | |
| rs3406379255 | 69 | Q>P | No | EVA | |
| rs3406541828 | 71 | L>R | No | EVA | |
| rs3406522460 | 72 | R>S | No | EVA | |
| rs3389365099 | 76 | L>H | No | EVA | |
| rs3389383814 | 89 | L>HG* | No | EVA | |
| rs3389392872 | 89 | L>V | No | EVA | |
| rs3389382643 | 90 | E>Q | No | EVA | |
| rs3389347310 | 95 | E>K | No | EVA | |
| rs3389356248 | 107 | H>Q | No | EVA | |
| rs3405666290 | 142 | L>P | No | EVA | |
| rs3389392856 | 169 | K>T | No | EVA | |
| rs3406686561 | 209 | S>A | No | EVA | |
| rs3405596517 | 209 | S>C | No | EVA | |
| rs3389304229 | 224 | P>H | No | EVA | |
| rs3389400915 | 228 | R>C | No | EVA | |
| rs3389378862 | 232 | E>* | No | EVA | |
| rs3406582519 | 264 | E>D | No | EVA | |
| rs3406582507 | 264 | E>G | No | EVA | |
| rs3389380027 | 296 | H>Q | No | EVA | |
| rs3389382611 | 297 | G>D | No | EVA | |
| rs3389383458 | 321 | R>Q | No | EVA | |
| rs3389376167 | 327 | L>I | No | EVA | |
| rs3412825742 | 329 | E>K | No | EVA | |
| rs3389383464 | 391 | G>D | No | EVA | |
| rs3389400920 | 395 | K>T | No | EVA | |
| rs3389337150 | 412 | D>G | No | EVA | |
| rs3389380067 | 413 | P>L | No | EVA | |
| rs3389376161 | 423 | L>R | No | EVA | |
| rs3389383393 | 426 | S>G | No | EVA | |
| rs3389383384 | 444 | V>A | No | EVA | |
| rs3389304210 | 450 | A>T | No | EVA | |
| rs32066074 | 457 | H>R | No | EVA | |
| rs3389387421 | 463 | N>K | No | EVA | |
| rs240551700 | 482 | M>V | No | EVA | |
| rs222584154 | 491 | S>N | No | EVA | |
| rs3389395771 | 501 | S>I | No | EVA | |
| rs3389382664 | 507 | S>I | No | EVA | |
| rs3406208438 | 540 | P>F | No | EVA | |
| rs3389380038 | 553 | S>R | No | EVA | |
| rs230524337 | 554 | A>T | No | EVA | |
| rs3389376142 | 561 | D>N | No | EVA | |
| rs3389376139 | 567 | I>T | No | EVA | |
| rs3389378874 | 589 | M>I | No | EVA | |
| rs3389388121 | 603 | V>M | No | EVA | |
| rs3389365076 | 614 | V>I | No | EVA | |
| rs51744165 | 621 | R>H | No | EVA | |
| rs3389383415 | 635 | V>L | No | EVA | |
| rs3389388170 | 642 | H>Q | No | EVA | |
| rs3389387480 | 670 | A>V | No | EVA | |
| rs3389395837 | 683 | R>G | No | EVA | |
| rs3389392862 | 685 | H>N | No | EVA | |
| rs3389365014 | 710 | Q>P | No | EVA | |
| rs3389347318 | 721 | P>L | No | EVA | |
| rs1135135476 | 779 | Y>H | No | EVA | |
| rs3389356286 | 781 | A>T | No | EVA | |
| rs3389392859 | 806 | V>I | No | EVA | |
| rs3389347324 | 837 | M>V | No | EVA | |
| rs3389347339 | 863 | S>N | No | EVA | |
| rs3389400969 | 871 | D>Y | No | EVA | |
| rs3389392924 | 885 | L>P | No | EVA |
No associated diseases with Q8VCC8
16 GO annotations of cellular component
| Name | Definition |
|---|---|
| apical part of cell | The region of a polarized cell that forms a tip or is distal to a base. For example, in a polarized epithelial cell, the apical region has an exposed surface and lies opposite to the basal lamina that separates the epithelium from other tissue. |
| axon terminus | Terminal inflated portion of the axon, containing the specialized apparatus necessary to release neurotransmitters. The axon terminus is considered to be the whole region of thickening and the terminal button is a specialized region of it. |
| basal plasma membrane | The region of the plasma membrane located at the basal end of the cell. Often used in reference to animal polarized epithelial membranes, where the basal membrane is the part attached to the extracellular matrix, or in plant cells, where the basal membrane is defined with respect to the zygotic axis. |
| basolateral part of cell | The region of a cell situated by the cell sides which interface adjacent cells and near the base. Often used in reference to animal polarized epithelial cells. |
| brush border membrane | The portion of the plasma membrane surrounding the brush border. |
| cortical actin cytoskeleton | The portion of the actin cytoskeleton, comprising filamentous actin and associated proteins, that lies just beneath the plasma membrane. |
| filopodium | Thin, stiff, actin-based protrusion extended by the leading edge of a motile cell such as a crawling fibroblast or amoeba, or an axonal or dendritic growth cone, or a dendritic shaft. |
| growth cone | The migrating motile tip of a growing neuron projection, where actin accumulates, and the actin cytoskeleton is the most dynamic. |
| lamellipodium | A thin sheetlike process extended by the leading edge of a migrating cell or extending cell process; contains a dense meshwork of actin filaments. |
| microvillus | Thin cylindrical membrane-covered projections on the surface of an animal cell containing a core bundle of actin filaments. Present in especially large numbers on the absorptive surface of intestinal cells. |
| neuronal cell body | The portion of a neuron that includes the nucleus, but excludes cell projections such as axons and dendrites. |
| perinuclear region of cytoplasm | Cytoplasm situated near, or occurring around, the nucleus. |
| photoreceptor cell terminal bouton | A specialized region of the axon terminus portion of a photoreceptor cell axon. A photoreceptor cell is a neuron specialized to detect and transduce light. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
| ribbon synapse | Type of synapse characterized by an electron-dense ribbon, lamella (bar) or spherical body in the presynaptic process cytoplasm. |
| rod bipolar cell terminal bouton | A specialized region of the axon terminus portion of a rod bipolar axon. A rod bipolar cell is a neuron found in the retina and having connections with rod photoreceptor cells and neurons in the inner plexiform layer. |
4 GO annotations of molecular function
| Name | Definition |
|---|---|
| cAMP binding | Binding to cAMP, the nucleotide cyclic AMP (adenosine 3',5'-cyclophosphate). |
| guanyl-nucleotide exchange factor activity | Stimulates the exchange of GDP to GTP on a signaling GTPase, changing its conformation to its active form. Guanine nucleotide exchange factors (GEFs) act by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP), which is more abundant in the cell under normal cellular physiological conditions. |
| protein domain specific binding | Binding to a specific domain of a protein. |
| transmembrane transporter binding | Binding to a transmembrane transporter, a protein or protein complex that enables the transfer of a substance, usually a specific substance or a group of related substances, from one side of a membrane to the other. |
21 GO annotations of biological process
| Name | Definition |
|---|---|
| angiogenesis | Blood vessel formation when new vessels emerge from the proliferation of pre-existing blood vessels. |
| associative learning | Learning by associating a stimulus (the cause) with a particular outcome (the effect). |
| cellular response to cAMP | Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a cAMP (cyclic AMP, adenosine 3',5'-cyclophosphate) stimulus. |
| establishment of endothelial barrier | The establishment of a barrier between endothelial cell layers, such as those in the brain, lung or intestine, to exert specific and selective control over the passage of water and solutes, thus allowing formation and maintenance of compartments that differ in fluid and solute composition. |
| negative regulation of cardiac muscle cell apoptotic process | Any process that decreases the rate or extent of cardiac cell apoptotic process, a form of programmed cell death induced by external or internal signals that trigger the activity of proteolytic caspases whose actions dismantle a cardiac muscle cell and result in its death. |
| negative regulation of collagen biosynthetic process | Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of collagen, any of a group of fibrous proteins of very high tensile strength that form the main component of connective tissue in animals. |
| negative regulation of syncytium formation by plasma membrane fusion | Any process that decreases the frequency, rate or extent of the formation of a syncytium, a mass of cytoplasm containing several nuclei enclosed within a single plasma membrane, by the fusion of the plasma membranes of two or more individual cells. |
| positive regulation of angiogenesis | Any process that activates or increases angiogenesis. |
| positive regulation of calcium ion transmembrane transport | Any process that activates or increases the frequency, rate or extent of calcium ion transmembrane transport. |
| positive regulation of cell size | Any process that increases cell size. |
| positive regulation of GTPase activity | Any process that activates or increases the activity of a GTPase. |
| positive regulation of protein export from nucleus | Any process that activates or increases the frequency, rate or extent of directed movement of proteins from the nucleus into the cytoplasm. |
| positive regulation of protein phosphorylation | Any process that activates or increases the frequency, rate or extent of addition of phosphate groups to amino acids within a protein. |
| positive regulation of smooth muscle cell migration | Any process that activates, maintains or increases the frequency, rate or extent of smooth muscle cell migration. |
| positive regulation of stress fiber assembly | Any process that activates or increases the frequency, rate or extent of the assembly of a stress fiber, a bundle of microfilaments and other proteins found in fibroblasts. |
| positive regulation of syncytium formation by plasma membrane fusion | Any process that increases the frequency, rate or extent of the formation of a syncytium, a mass of cytoplasm containing several nuclei enclosed within a single plasma membrane, by the fusion of the plasma membranes of two or more individual cells. |
| positive regulation of transcription by RNA polymerase II | Any process that activates or increases the frequency, rate or extent of transcription from an RNA polymerase II promoter. |
| Rap protein signal transduction | The series of molecular signals within the cell that are mediated by a member of the Rap family of proteins switching to a GTP-bound active state. |
| Ras protein signal transduction | The series of molecular signals within the cell that are mediated by a member of the Ras superfamily of proteins switching to a GTP-bound active state. |
| regulation of actin cytoskeleton organization | Any process that modulates the frequency, rate or extent of the formation, arrangement of constituent parts, or disassembly of cytoskeletal structures comprising actin filaments and their associated proteins. |
| regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | Any process that modulates the frequency, rate or extent of protein kinase B signaling, a series of reactions mediated by the intracellular serine/threonine kinase protein kinase B. |
13 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| Q8WZA2 | RAPGEF4 | Rap guanine nucleotide exchange factor 4 | Homo sapiens (Human) | SS |
| O95398 | RAPGEF3 | Rap guanine nucleotide exchange factor 3 | Homo sapiens (Human) | EV |
| Q02384 | Sos2 | Son of sevenless homolog 2 | Mus musculus (Mouse) | SS |
| Q62245 | Sos1 | Son of sevenless homolog 1 | Mus musculus (Mouse) | SS |
| Q9EQZ6 | Rapgef4 | Rap guanine nucleotide exchange factor 4 | Mus musculus (Mouse) | EV |
| Q9D300 | Rasgef1c | Ras-GEF domain-containing family member 1C | Mus musculus (Mouse) | PR |
| Q03385 | Ralgds | Ral guanine nucleotide dissociation stimulator | Mus musculus (Mouse) | PR |
| Q9Z1S3 | Rasgrp1 | RAS guanyl-releasing protein 1 | Mus musculus (Mouse) | SS |
| Q8BTM9 | Rasgrp4 | RAS guanyl-releasing protein 4 | Mus musculus (Mouse) | SS |
| Q9QUG9 | Rasgrp2 | RAS guanyl-releasing protein 2 | Mus musculus (Mouse) | SS |
| Q9ERD6 | Ralgps2 | Ras-specific guanine nucleotide-releasing factor RalGPS2 | Mus musculus (Mouse) | PR |
| A2AR50 | Ralgps1 | Ras-specific guanine nucleotide-releasing factor RalGPS1 | Mus musculus (Mouse) | PR |
| Q9Z1C8 | Rapgef3 | Rap guanine nucleotide exchange factor 3 | Rattus norvegicus (Rat) | SS |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MKVSWPGENH | WQVGPAVVES | PAVGAPQVGG | LPDVVPEGTL | LNMVLKRMHR | PRCCSYQLVF |
| 70 | 80 | 90 | 100 | 110 | 120 |
| EHRRPSCIQG | LRWTPLTNSE | DSLDFRVSLE | QATTEHVHKA | GKLLHRHLLA | TYPTLIRDRK |
| 130 | 140 | 150 | 160 | 170 | 180 |
| YHLRLYRHCC | SGRELVDGIL | ALGLGVHSRS | QAVGICQVLL | DEGALCHVKH | DWTFQDRDAQ |
| 190 | 200 | 210 | 220 | 230 | 240 |
| FYRFPGPEPE | PTGTQDVEEE | LVEAMALLSQ | RGPDALLTVA | LRKPPGQRTD | EELDLIFEEL |
| 250 | 260 | 270 | 280 | 290 | 300 |
| LHIKAVAHLS | NSVKRELAAV | LLFEPHSKAG | TVLFSQGDKG | TSWYIIWKGS | VNVVTHGKGL |
| 310 | 320 | 330 | 340 | 350 | 360 |
| VTTLHEGDDF | GQLALVNDAP | RAATIILREN | NCHFLRVDKQ | DFNRIIKDVE | AKTMRLEEHG |
| 370 | 380 | 390 | 400 | 410 | 420 |
| KVVLVLERTS | QGAGPSRPPT | PGRNRYTVMS | GTPEKILELL | LEAMRPDSSA | HDPTETFLSD |
| 430 | 440 | 450 | 460 | 470 | 480 |
| FLLTHSVFMP | STQLFTALLH | HFHVEPADPA | GGSEQEHSTY | ICNKRQQILR | LVGRWVALYS |
| 490 | 500 | 510 | 520 | 530 | 540 |
| PMLHSDPVAT | SFLQKLSDLV | SRDARLSNLL | REQYPERRRH | HRLENGCGNV | SPQTKARNAP |
| 550 | 560 | 570 | 580 | 590 | 600 |
| VWLPNQEEPL | PSSAGAIRVG | DKVPYDICRP | DHSVLTLHLP | VTASVREVMA | ALAHEDHWTK |
| 610 | 620 | 630 | 640 | 650 | 660 |
| GQVLVKVNSA | GDVVGLQPDA | RGVATSLGLN | ERLFVVDPQE | VHELTPHPEQ | LGPTLGSSEM |
| 670 | 680 | 690 | 700 | 710 | 720 |
| LDLVSAKDLA | GQLTDHDWNL | FNRIHQVQEH | LRDVTTANLE | RFMRRFNELQ | YWVATELCLC |
| 730 | 740 | 750 | 760 | 770 | 780 |
| PVPGSRAQLL | RKFIKLAAHL | KEQKNLNSFF | AVMFGLSNSA | ISRLAHTWER | LPHKVRKLYS |
| 790 | 800 | 810 | 820 | 830 | 840 |
| ALERLLDPSW | NHRVYRLALT | KLSPPVIPFM | PLLLKDVTFI | HEGNHTLVEN | LINFEKMRMM |
| 850 | 860 | 870 | 880 | 890 | 900 |
| ARAVRMLHHC | RSHSTAPLSP | LRSRVSHIHE | DSQGSRISTC | SEQSLSTRSP | ASTWAYVQQL |
| 910 | |||||
| KVIDNQRELS | RLSRELEP |