MGP Database

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MGP003983

UniProt Annotations

Entry Information
Gene NameRap guanine nucleotide exchange factor (GEF) 2
Protein EntryRPGF2_HUMAN
UniProt IDQ9Y4G8
SpeciesHuman
Comments
Comment typeDescription
DomainThe Ras-associating domain is necessary for the Rap guanine nucleotide exchange activity. The N-terminal regionis necessary for cAMP-binding. The PDZ domain is necessary for its targeting to the cell membrane.
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}.
InteractionQ96QZ7-3:MAGI1; NbExp=2; IntAct=EBI-307079, EBI-8769674;
PtmPhosphorylation by PLK2 promotes its activity. {ECO:0000250}.
PtmUbiquitinated by NEDD4, leading to proteasomal degradation. {ECO:0000269|PubMed:11598133}.
Sequence CautionSequence=BAA20772.2; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
SimilarityBelongs to the RAPGEF2 family. {ECO:0000305}.
SimilarityContains 1 cyclic nucleotide-binding domain. {ECO:0000255|PROSITE-ProRule:PRU00060}.
SimilarityContains 1 N-terminal Ras-GEF domain. {ECO:0000255|PROSITE-ProRule:PRU00135, ECO:0000305}.
SimilarityContains 1 PDZ (DHR) domain. {ECO:0000255|PROSITE- ProRule:PRU00143}.
SimilarityContains 1 Ras-associating domain. {ECO:0000255|PROSITE-ProRule:PRU00166}.
SimilarityContains 1 Ras-GEF domain. {ECO:0000255|PROSITE- ProRule:PRU00168, ECO:0000305}.
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}.
SubunitInteracts with CDH1, CTNNB1 and TJP1 (By similarity). Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains); the interaction occurs before or after NGF stimulation. Interacts with KIDINS220 and NTRK1; the interactions occur after NGF stimulation (By similarity). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a neuronal growth factor (NGF)- dependent manner. Interacts (via C-terminal domain) with NEDD4 (via WW domains); this interaction leads to ubiquitination and degradation via the proteasome pathway in a cAMP-independent manner. Interacts with MAGI1 isoform 3 (via PDZ domain). Interacts with ADRB1 (via C-terminal PDZ motif); the interaction is direct. Interacts (via Ras-associating domain) with RAP1A (via GTP-bound active form). Interacts weakly with HRAS (via GDP- and GTP-bound forms). Interacts (via C-terminal domain) with MAGI2 (via PDZ and WW domains). {ECO:0000250, ECO:0000269|PubMed:10548487, ECO:0000269|PubMed:10608844, ECO:0000269|PubMed:11168587, ECO:0000269|PubMed:11359771, ECO:0000269|PubMed:11598133, ECO:0000269|PubMed:12391161, ECO:0000269|PubMed:17724123}.
Tissue SpecificityExpressed 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. {ECO:0000269|PubMed:10934204, ECO:0000269|PubMed:11168587, ECO:0000269|PubMed:23800469}.
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