InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: RAPGEF2

Summary

InnateDB Protein

IDBP-43119.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

RAPGEF2

Protein Name

Rap guanine nucleotide exchange factor (GEF) 2

Synonyms

CNrasGEF; nRap GEP; NRAPGEP; PDZ-GEF1; PDZGEF1; RA-GEF; RA-GEF-1; Rap-GEP;

Species

Homo sapiens

Ensembl Protein

ENSP00000264431

InnateDB Gene

IDBG-43117 (RAPGEF2)

Protein Structure

UniProt Annotation

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:0000269PubMed:10548487, ECO:0000269PubMed:10608844, ECO:0000269PubMed:10608883, ECO:0000269PubMed:10801446, ECO:0000269PubMed:10934204, ECO:0000269PubMed:11359771, ECO:0000269PubMed:12391161, ECO:0000269PubMed:16272156, ECO:0000269PubMed:17724123, ECO:0000269PubMed:21840392, ECO:0000269PubMed:23800469}.

Subcellular Localization

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}.

Disease Associations

Tissue Specificity

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. {ECO:0000269PubMed:10934204, ECO:0000269PubMed:11168587, ECO:0000269PubMed:23800469}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 25 experimentally validated interaction(s) in this database.
They are also associated with 1 interaction(s) predicted by orthology.

Experimentally validated
Total	25 [view]
Protein-Protein	25 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	1 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004871	signal transducer activity
GO:0005085	guanyl-nucleotide exchange factor activity
GO:0005088	Ras guanyl-nucleotide exchange factor activity
GO:0005509	calcium ion binding
GO:0005515	protein binding
GO:0017034	Rap guanyl-nucleotide exchange factor activity
GO:0019901	protein kinase binding
GO:0019992	diacylglycerol binding
GO:0030165	PDZ domain binding
GO:0030552	cAMP binding
GO:0031697	beta-1 adrenergic receptor binding
GO:0046582	Rap GTPase activator activity
GO:0050699	WW domain binding

Biological Process

GO:0000165	MAPK cascade
GO:0001568	blood vessel development
GO:0001764	neuron migration
GO:0007165	signal transduction
GO:0007186	G-protein coupled receptor signaling pathway
GO:0007218	neuropeptide signaling pathway
GO:0007264	small GTPase mediated signal transduction
GO:0008285	negative regulation of cell proliferation
GO:0010976	positive regulation of neuron projection development
GO:0019933	cAMP-mediated signaling
GO:0021591	ventricular system development
GO:0021884	forebrain neuron development
GO:0031175	neuron projection development
GO:0031547	brain-derived neurotrophic factor receptor signaling pathway
GO:0032092	positive regulation of protein binding
GO:0032320	positive regulation of Ras GTPase activity
GO:0032486	Rap protein signal transduction
GO:0032854	positive regulation of Rap GTPase activity
GO:0035556	intracellular signal transduction
GO:0038180	nerve growth factor signaling pathway
GO:0043950	positive regulation of cAMP-mediated signaling
GO:0045860	positive regulation of protein kinase activity
GO:0048022	negative regulation of melanin biosynthetic process
GO:0048167	regulation of synaptic plasticity
GO:0050774	negative regulation of dendrite morphogenesis
GO:0051056	regulation of small GTPase mediated signal transduction
GO:0061028	establishment of endothelial barrier
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0071320	cellular response to cAMP
GO:0071321	cellular response to cGMP
GO:0071880	adenylate cyclase-activating adrenergic receptor signaling pathway
GO:1901888	regulation of cell junction assembly
GO:1990090	cellular response to nerve growth factor stimulus
GO:2000481	positive regulation of cAMP-dependent protein kinase activity
GO:2000670	positive regulation of dendritic cell apoptotic process
GO:2001214	positive regulation of vasculogenesis
GO:2001224	positive regulation of neuron migration

Cellular Component

GO:0005622	intracellular
GO:0005737	cytoplasm
GO:0005770	late endosome
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005911	cell-cell junction
GO:0016020	membrane
GO:0043005	neuron projection
GO:0043025	neuronal cell body
GO:0043234	protein complex
GO:0045202	synapse
GO:0048471	perinuclear region of cytoplasm

Protein Structure and Domains

PDB ID

InterPro

IPR000159 Ras-association
IPR000595 Cyclic nucleotide-binding domain
IPR000651 Ras-like guanine nucleotide exchange factor, N-terminal
IPR001478 PDZ domain
IPR001895 Ras guanine-nucleotide exchange factors catalytic domain
IPR018490 Cyclic nucleotide-binding-like
IPR023578 Ras guanine nucleotide exchange factor domain
IPR029071 Ubiquitin-related domain

PFAM

PF00788
PF00027
PF00618
PF00595
PF13180
PF00617

PRINTS

PIRSF

SMART

SM00314
SM00100
SM00229
SM00228
SM00147

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt

Q9Y4G8